Benzodiazepine overdose
Encyclopedia
Benzodiazepine
overdose
describes the ingestion of one of the drugs in the benzodiazepine class in quantities greater than are recommended or generally practiced. Death as a result of benzodiazepines is uncommon but does occasionally happen. Deaths after hospital admission are considered to be low. However, combinations of high doses of benzodiazepines with alcohol
, barbiturates, opioids or tricyclic antidepressants are particularly dangerous, and may lead to severe complications such as coma
or death. The most common symptoms of overdose include central nervous system
(CNS) depression and intoxication with impaired balance, ataxia
, and slurred speech. Severe symptoms include coma
and respiratory depression. Supportive care is the mainstay of treatment of benzodiazepine overdose. There is an antidote, flumazenil
, but its use is controversial.
As benzodiazepines are one of the most highly prescribed class of drugs they are commonly used in self-poisoning by drug overdose
. The various benzodiazepines differ in their toxicity since they produce varying levels of sedation in overdose. A 1993 British study of deaths during the 1980s found flurazepam
and temazepam
more frequently involved in drug-related deaths causing more deaths per million prescriptions than other benzodiazepines. Flurazepam, now rarely prescribed in the United Kingdom and Australia, had the highest fatal toxicity index of any benzodiazepine (15.0), followed by temazepam (11.9), vs. benzodiazepines overall (5.9), taken with or without alcohol. An Australian (1995) study found oxazepam
being less toxic and less sedative and temazepam more toxic and more sedative than most benzodiazepines in overdose. An Australian study (2004) of overdose admissions between 1987 and 2002 found alprazolam
, which happens to be the most prescribed benzodiazepine in the U.S. by a large margin, to be more toxic than diazepam and other benzodiazepines. They also cited a review of the Annual Reports of the American Association of Poison Control Centers National Data Collection System, which showed alprazolam was involved in 34 fatal deliberate self poisonings over 10 years 1992–2001, compared with 30 fatal deliberate self poisonings involving diazepam. In a New Zealand study (2003) of 200 deaths Zopiclone
, a benzodiazepine receptor agonist
had similar overdose potential as benzodiazepines.
overdose of a benzodiazepine the onset of symptoms is typically rapid with most developing symptoms within 4 hours. Patients initially present with mild to moderate impairment of central nervous system
function. Initial signs and symptoms include intoxication, somnolence
, diplopia
, impaired balance, impaired motor function, anterograde amnesia
, ataxia
, and slurred speech. Most patients with pure benzodiazepine overdose will usually only exhibit these mild CNS symptoms. Paradoxical reactions such as anxiety
, delirium
, combativeness, hallucination
s, and aggression can also occur following benzodiazepine overdose. Gastrointestinal symptoms such as nausea and vomiting have also been occasionally reported.
Cases of severe overdose have been reported and symptoms displayed may include prolonged deep coma or deep cyclic coma, apnea
, respiratory depression, hypoxemia
, hypothermia
, hypotension
, bradycardia
, cardiac arrest
, and pulmonary aspiration
, with the possibility of death. Severe consequences are rare following overdose of benzodiazepines alone but the severity of overdose is increased significantly if benzodiazepines are taken in overdose in combination with other medications. Significant toxicity may result following recreation drug misuse
in conjunction with other CNS depressants
such as opioids or ethanol
. The duration of symptoms following overdose is usually between 12 and 36 hours in the majority of cases. The majority of drug-related deaths involve misuse of heroin or other opioids in combination with benzodiazepines or other CNS depressant drugs. In most cases of fatal overdose it is likely that lack of opioid tolerance combined with the depressant effects of benzodiazepines is the cause of death.
The symptoms of an overdose such as sleepiness, agitation
and ataxia
occur much more frequently and severely in children. Hypotonia
may also occur in severe cases.
and taken alone in overdose
rarely cause severe complications or fatalities. They are, however, not devoid of serious toxicity and cases of severe coma or fatality have been reported. Taken in overdose in combination with alcohol
, barbiturates, opioids, tricyclic antidepressants, or sedating antipsychotic
s, anticonvulsant
s, or antihistamine
s are particularly dangerous. In the case of alcohol and barbiturates, not only do they have an additive effect but they also increase the binding affinity of benzodiazepines to the benzodiazepine binding site
, which results in a very significant potentiation of the CNS and respiratory depressant effects. In addition, the elderly and those with chronic illnesses are much more vulnerable to lethal overdose with benzodiazepines. Fatal overdoses can occur at relatively low doses in these individuals.
(GABA) and causing CNS depression. In overdose situations this pharmacological effect is extended leading to a more severe CNS depression and potentially coma. Benzodiazepine overdose related coma
may be characterised by an alpha pattern with the central somatosensory conduction time (CCT) after median nerve stimulation being prolonged and the N20 to be dispersed. Brain-stem
auditory evoked potentials demonstrate delayed interpeak latencies (IPLs) I-III, III-V and I-V. Toxic overdoses therefore of benzodiazepines cause prolonged CCT and IPLs.
, gas liquid chromatography with or without a mass spectrometer, and radioimmunoassay
. Blood benzodiazepine concentrations, however, do not appear to be related to any toxicological effect or predictive of clinical outcome. Blood concentrations are, therefore, used mainly to confirm the diagnosis rather than being useful for the clinical management of the patient.
Medical observation and supportive care are the mainstay of treatment of benzodiazepine overdose. Although benzodiazepines are absorbed by activated charcoal, gastric decontamination with activated charcoal is not beneficial in pure benzodiazepine overdose as the risk of adverse effects would outweigh any potential benefit from the procedure. It is recommended only if benzodiazepines have been taken in combination with other drugs that may benefit from decontamination. Gastric lavage
(stomach pumping) or whole bowel irrigation
are also not recommended. Enhancing elimination
of the drug with hemodialysis
, hemoperfusion
, or forced diuresis
is unlikely to be beneficial as these procedures have little effect on the clearance
of benzodiazepines due to their large volume of distribution
and lipid solubility.
, especially Glasgow Coma Scale
and airway patency. IV access with fluid administration and maintenance of the airway with intubation
and artificial ventilation may be required if respiratory depression or pulmonary aspiration occurs. Supportive measures should be put in place prior to administration of any benzodiazepine antagonist in order to protect the patient from both the withdrawal effects and possible complications arising from the benzodiazepine. A determination of possible deliberate overdose should be considered with appropriate scrutiny, and precautions taken to prevent any attempt by the patient to commit further bodily harm. Hypotension is corrected with fluid replacement, although catecholamine
s such as norepinephrine
or dopamine
may be required to increase blood pressure
. Bradycardia
is treated with atropine
or an infusion of norepinephrine to increase coronary blood flow
and heart rate
.
(Anexate) is a competitive benzodiazepine receptor antagonist
that can be used as an antidote
for benzodiazepine overdose. Its use, however, is controversial as it has numerous contraindications. It is contraindicated in patients who are on long-term benzodiazepines, those who have ingested a substance that lowers the seizure threshold
, or in patients who have tachycardia, widened QRS complex
on ECG, anticholinergic
signs, or a history of seizures. Due to these contraindications and the possibility of it causing severe adverse effects including seizures, adverse cardiac effects, and death, in the majority of cases there is no indication for the use of flumazenil in the management of benzodiazepine overdose as the risks in general outweigh any potential benefit of administration. It also has no role in the management of an unknown overdoses. In addition, if full airway protection has been achieved, a good outcome is expected, and therefore flumazenil administration is unlikely to be required.
Flumazenil is very effective at reversing the CNS depression
associated with benzodiazepines but is less effective at reversing respiratory depression. One study found that only 10% of the patient population presenting with a benzodiazepine overdose are suitable candidates for flumazenil. In this select population who are naive to and overdose solely on a benzodiazepine, it can be considered. Due to its short half life
, the duration of action of flumazenil is usually less than 1 hour, and multiple doses may be needed. When flumazenil is indicated the risks can be reduced or avoided by slow dose titration of flumazenil. Due to risks and its many contraindications, flumazenil should be administered only after discussion with a medical toxicologist
.
and flunitrazepam
accounted for 90% of benzodiazepine implicated suicides. In cases, where benzodiazepines contributed to death, but were not the sole cause, drowning, typically in the bath, was a common method used. Benzodiazepines were the predominant drug class in suicides in this review of Swedish death certificates. In 72% of the cases, benzodiazepines were the only drug consumed. Thus, many of deaths associated with benzodiazepine overdoses may not be a direct result of the toxic effects but either due to being combined with other drugs or used as a tool to complete suicide using a different method, e.g. drowning.
In a Swedish retrospective study of deaths of 1987, in 159 of 1587 autopsy cases benzodiazepines were found. In 44 of these cases the cause of death was natural causes
or unclear. The remaining 115 deaths were due to accidents (N = 16), suicide (N = 60), drug addiction (N = 29) or alcoholism
(N = 10). In a comparison of suicides and natural deaths, the concentrations both of flunitrazepam and nitrazepam (sleeping medications) were significantly higher among the suicides.
In four cases benzodiazepines were the sole cause of death.
In Australia, a study of 16 deaths associated with toxic concentrations of benzodiazepines during the period of 5 years leading up to July 1994 found preexisting natural disease as a feature of 11 cases; 14 cases were suicides. Cases where other drugs, including ethanol, had contributed to the death were excluded. In the remaining five cases, death was caused solely by benzodiazepines. Nitrazepam and temazepam were the most prevalent drugs detected, followed by oxazepam and flunitrazepam. A review of self poisonings of 12 months 1976 - 1977 in Auckland
, New Zealand
, found benzodiazepines implicated in 40% of the cases. A 1993 British study found flurazepam and temazepam to have the highest number of deaths per million prescriptions among medications commonly prescribed in the 1980s. Flurazepam, now rarely prescribed in the United Kingdom and Australia, had the highest fatal toxicity index of any benzodiazepine (15.0) followed by Temazepam (11.9), versus 5.9 for benzodiazepines overall, taken with or without alcohol.
Benzodiazepine
A benzodiazepine is a psychoactive drug whose core chemical structure is the fusion of a benzene ring and a diazepine ring...
overdose
Drug overdose
The term drug overdose describes the ingestion or application of a drug or other substance in quantities greater than are recommended or generally practiced...
describes the ingestion of one of the drugs in the benzodiazepine class in quantities greater than are recommended or generally practiced. Death as a result of benzodiazepines is uncommon but does occasionally happen. Deaths after hospital admission are considered to be low. However, combinations of high doses of benzodiazepines with alcohol
Ethanol
Ethanol, also called ethyl alcohol, pure alcohol, grain alcohol, or drinking alcohol, is a volatile, flammable, colorless liquid. It is a psychoactive drug and one of the oldest recreational drugs. Best known as the type of alcohol found in alcoholic beverages, it is also used in thermometers, as a...
, barbiturates, opioids or tricyclic antidepressants are particularly dangerous, and may lead to severe complications such as coma
Coma
In medicine, a coma is a state of unconsciousness, lasting more than 6 hours in which a person cannot be awakened, fails to respond normally to painful stimuli, light or sound, lacks a normal sleep-wake cycle and does not initiate voluntary actions. A person in a state of coma is described as...
or death. The most common symptoms of overdose include central nervous system
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
(CNS) depression and intoxication with impaired balance, ataxia
Ataxia
Ataxia is a neurological sign and symptom that consists of gross lack of coordination of muscle movements. Ataxia is a non-specific clinical manifestation implying dysfunction of the parts of the nervous system that coordinate movement, such as the cerebellum...
, and slurred speech. Severe symptoms include coma
Coma
In medicine, a coma is a state of unconsciousness, lasting more than 6 hours in which a person cannot be awakened, fails to respond normally to painful stimuli, light or sound, lacks a normal sleep-wake cycle and does not initiate voluntary actions. A person in a state of coma is described as...
and respiratory depression. Supportive care is the mainstay of treatment of benzodiazepine overdose. There is an antidote, flumazenil
Flumazenil
Flumazenil is a benzodiazepine antagonist available for injection only, and the only benzodiazepine receptor antagonist on the market today.It was first introduced in 1987 by Hoffmann-La Roche under the trade name Anexate, but only approved by...
, but its use is controversial.
As benzodiazepines are one of the most highly prescribed class of drugs they are commonly used in self-poisoning by drug overdose
Drug overdose
The term drug overdose describes the ingestion or application of a drug or other substance in quantities greater than are recommended or generally practiced...
. The various benzodiazepines differ in their toxicity since they produce varying levels of sedation in overdose. A 1993 British study of deaths during the 1980s found flurazepam
Flurazepam
Flurazepam is a drug which is a benzodiazepine derivative. It possesses anxiolytic, anticonvulsant, sedative and skeletal muscle relaxant properties. It produces a metabolite with a very long half-life , which may stay in the bloodstream for up to four days...
and temazepam
Temazepam
Temazepam is an intermediate-acting 3-hydroxy benzodiazepine. It is mostly prescribed for the short-term treatment of sleeplessness in patients who have difficulty maintaining sleep...
more frequently involved in drug-related deaths causing more deaths per million prescriptions than other benzodiazepines. Flurazepam, now rarely prescribed in the United Kingdom and Australia, had the highest fatal toxicity index of any benzodiazepine (15.0), followed by temazepam (11.9), vs. benzodiazepines overall (5.9), taken with or without alcohol. An Australian (1995) study found oxazepam
Oxazepam
Oxazepam , is a drug which is a short to intermediate acting 3-hydroxy benzodiazepine derivative...
being less toxic and less sedative and temazepam more toxic and more sedative than most benzodiazepines in overdose. An Australian study (2004) of overdose admissions between 1987 and 2002 found alprazolam
Alprazolam
Alprazolam is a short-acting anxiolytic of the benzodiazepine class of psychoactive drugs. Alprazolam, like other benzodiazepines, binds to specific sites on the GABAA gamma-amino-butyric acid receptor...
, which happens to be the most prescribed benzodiazepine in the U.S. by a large margin, to be more toxic than diazepam and other benzodiazepines. They also cited a review of the Annual Reports of the American Association of Poison Control Centers National Data Collection System, which showed alprazolam was involved in 34 fatal deliberate self poisonings over 10 years 1992–2001, compared with 30 fatal deliberate self poisonings involving diazepam. In a New Zealand study (2003) of 200 deaths Zopiclone
Zopiclone
Zopiclone is a non-benzodiazepine hypnotic agent used in the treatment of insomnia. In the United States, zopiclone is not commercially available, although its active stereoisomer, eszopiclone, is sold under the name Lunesta...
, a benzodiazepine receptor agonist
Agonist
An agonist is a chemical that binds to a receptor of a cell and triggers a response by that cell. Agonists often mimic the action of a naturally occurring substance...
had similar overdose potential as benzodiazepines.
Signs and symptoms
Following an acuteAcute toxicity
Acute toxicity describes the adverse effects of a substance that result either from a single exposure or from multiple exposures in a short space of time...
overdose of a benzodiazepine the onset of symptoms is typically rapid with most developing symptoms within 4 hours. Patients initially present with mild to moderate impairment of central nervous system
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
function. Initial signs and symptoms include intoxication, somnolence
Somnolence
Somnolence is a state of near-sleep, a strong desire for sleep, or sleeping for unusually long periods . It has two distinct meanings, referring both to the usual state preceding falling asleep, and the chronic condition referring to being in that state independent of a circadian rhythm...
, diplopia
Diplopia
Diplopia, commonly known as double vision, is the simultaneous perception of two images of a single object that may be displaced horizontally, vertically, or diagonally in relation to each other...
, impaired balance, impaired motor function, anterograde amnesia
Anterograde amnesia
Anterograde amnesia is a loss of the ability to create new memories after the event that caused the amnesia, leading to a partial or complete inability to recall the recent past, while long-term memories from before the event remain intact. This is in contrast to retrograde amnesia, where memories...
, ataxia
Ataxia
Ataxia is a neurological sign and symptom that consists of gross lack of coordination of muscle movements. Ataxia is a non-specific clinical manifestation implying dysfunction of the parts of the nervous system that coordinate movement, such as the cerebellum...
, and slurred speech. Most patients with pure benzodiazepine overdose will usually only exhibit these mild CNS symptoms. Paradoxical reactions such as anxiety
Anxiety
Anxiety is a psychological and physiological state characterized by somatic, emotional, cognitive, and behavioral components. The root meaning of the word anxiety is 'to vex or trouble'; in either presence or absence of psychological stress, anxiety can create feelings of fear, worry, uneasiness,...
, delirium
Delirium
Delirium or acute confusional state is a common and severe neuropsychiatric syndrome with core features of acute onset and fluctuating course, attentional deficits and generalized severe disorganization of behavior...
, combativeness, hallucination
Hallucination
A hallucination, in the broadest sense of the word, is a perception in the absence of a stimulus. In a stricter sense, hallucinations are defined as perceptions in a conscious and awake state in the absence of external stimuli which have qualities of real perception, in that they are vivid,...
s, and aggression can also occur following benzodiazepine overdose. Gastrointestinal symptoms such as nausea and vomiting have also been occasionally reported.
Cases of severe overdose have been reported and symptoms displayed may include prolonged deep coma or deep cyclic coma, apnea
Apnea
Apnea, apnoea, or apnœa is a term for suspension of external breathing. During apnea there is no movement of the muscles of respiration and the volume of the lungs initially remains unchanged...
, respiratory depression, hypoxemia
Hypoxemia
Hypoxemia is generally defined as decreased partial pressure of oxygen in blood, sometimes specifically as less than or causing hemoglobin oxygen saturation of less than 90%.-Distinction from anemia and hypoxia:...
, hypothermia
Hypothermia
Hypothermia is a condition in which core temperature drops below the required temperature for normal metabolism and body functions which is defined as . Body temperature is usually maintained near a constant level of through biologic homeostasis or thermoregulation...
, hypotension
Hypotension
In physiology and medicine, hypotension is abnormally low blood pressure, especially in the arteries of the systemic circulation. It is best understood as a physiologic state, rather than a disease. It is often associated with shock, though not necessarily indicative of it. Hypotension is the...
, bradycardia
Bradycardia
Bradycardia , in the context of adult medicine, is the resting heart rate of under 60 beats per minute, though it is seldom symptomatic until the rate drops below 50 beat/min. It may cause cardiac arrest in some patients, because those with bradycardia may not be pumping enough oxygen to their heart...
, cardiac arrest
Cardiac arrest
Cardiac arrest, is the cessation of normal circulation of the blood due to failure of the heart to contract effectively...
, and pulmonary aspiration
Pulmonary aspiration
Pulmonary aspiration is the entry of material from the oropharynx or gastrointestinal tract into the larynx and lower respiratory tract...
, with the possibility of death. Severe consequences are rare following overdose of benzodiazepines alone but the severity of overdose is increased significantly if benzodiazepines are taken in overdose in combination with other medications. Significant toxicity may result following recreation drug misuse
Drug abuse
Substance abuse, also known as drug abuse, refers to a maladaptive pattern of use of a substance that is not considered dependent. The term "drug abuse" does not exclude dependency, but is otherwise used in a similar manner in nonmedical contexts...
in conjunction with other CNS depressants
Depressant
A depressant, or central depressant, is a drug or endogenous compound that depresses the function or activity of a specific part of the brain...
such as opioids or ethanol
Alcohol
In chemistry, an alcohol is an organic compound in which the hydroxy functional group is bound to a carbon atom. In particular, this carbon center should be saturated, having single bonds to three other atoms....
. The duration of symptoms following overdose is usually between 12 and 36 hours in the majority of cases. The majority of drug-related deaths involve misuse of heroin or other opioids in combination with benzodiazepines or other CNS depressant drugs. In most cases of fatal overdose it is likely that lack of opioid tolerance combined with the depressant effects of benzodiazepines is the cause of death.
The symptoms of an overdose such as sleepiness, agitation
Psychomotor agitation
Psychomotor agitation is a series of unintentional and purposeless motions that stem from mental tension and anxiety of an individual. This includes pacing around a room, wringing one's hands, pulling off clothing and putting it back on and other similar actions...
and ataxia
Ataxia
Ataxia is a neurological sign and symptom that consists of gross lack of coordination of muscle movements. Ataxia is a non-specific clinical manifestation implying dysfunction of the parts of the nervous system that coordinate movement, such as the cerebellum...
occur much more frequently and severely in children. Hypotonia
Hypotonia
Hypotonia is a state of low muscle tone , often involving reduced muscle strength. Hypotonia is not a specific medical disorder, but a potential manifestation of many different diseases and disorders that affect motor nerve control by the brain or muscle strength...
may also occur in severe cases.
Toxicity
Benzodiazepines have a wide therapeutic indexTherapeutic index
The therapeutic index is a comparison of the amount of a therapeutic agent that causes the therapeutic effect to the amount that causes death or toxicity ....
and taken alone in overdose
Drug overdose
The term drug overdose describes the ingestion or application of a drug or other substance in quantities greater than are recommended or generally practiced...
rarely cause severe complications or fatalities. They are, however, not devoid of serious toxicity and cases of severe coma or fatality have been reported. Taken in overdose in combination with alcohol
Ethanol
Ethanol, also called ethyl alcohol, pure alcohol, grain alcohol, or drinking alcohol, is a volatile, flammable, colorless liquid. It is a psychoactive drug and one of the oldest recreational drugs. Best known as the type of alcohol found in alcoholic beverages, it is also used in thermometers, as a...
, barbiturates, opioids, tricyclic antidepressants, or sedating antipsychotic
Antipsychotic
An antipsychotic is a tranquilizing psychiatric medication primarily used to manage psychosis , particularly in schizophrenia and bipolar disorder. A first generation of antipsychotics, known as typical antipsychotics, was discovered in the 1950s...
s, anticonvulsant
Anticonvulsant
The anticonvulsants are a diverse group of pharmaceuticals used in the treatment of epileptic seizures. Anticonvulsants are also increasingly being used in the treatment of bipolar disorder, since many seem to act as mood stabilizers, and in the treatment of neuropathic pain. The goal of an...
s, or antihistamine
Antihistamine
An H1 antagonist is a histamine antagonist of the H1 receptor that serves to reduce or eliminate effects mediated by histamine, an endogenous chemical mediator released during allergic reactions...
s are particularly dangerous. In the case of alcohol and barbiturates, not only do they have an additive effect but they also increase the binding affinity of benzodiazepines to the benzodiazepine binding site
Binding site
In biochemistry, a binding site is a region on a protein, DNA, or RNA to which specific other molecules and ions—in this context collectively called ligands—form a chemical bond...
, which results in a very significant potentiation of the CNS and respiratory depressant effects. In addition, the elderly and those with chronic illnesses are much more vulnerable to lethal overdose with benzodiazepines. Fatal overdoses can occur at relatively low doses in these individuals.
Pathophysiology
Benzodiazepines bind to a specific benzodiazepine receptor, thereby enhancing the effect of the neurotransmitter gamma-aminobutyric acidGamma-aminobutyric acid
γ-Aminobutyric acid is the chief inhibitory neurotransmitter in the mammalian central nervous system. It plays a role in regulating neuronal excitability throughout the nervous system...
(GABA) and causing CNS depression. In overdose situations this pharmacological effect is extended leading to a more severe CNS depression and potentially coma. Benzodiazepine overdose related coma
Coma
In medicine, a coma is a state of unconsciousness, lasting more than 6 hours in which a person cannot be awakened, fails to respond normally to painful stimuli, light or sound, lacks a normal sleep-wake cycle and does not initiate voluntary actions. A person in a state of coma is described as...
may be characterised by an alpha pattern with the central somatosensory conduction time (CCT) after median nerve stimulation being prolonged and the N20 to be dispersed. Brain-stem
Brain stem
In vertebrate anatomy the brainstem is the posterior part of the brain, adjoining and structurally continuous with the spinal cord. The brain stem provides the main motor and sensory innervation to the face and neck via the cranial nerves...
auditory evoked potentials demonstrate delayed interpeak latencies (IPLs) I-III, III-V and I-V. Toxic overdoses therefore of benzodiazepines cause prolonged CCT and IPLs.
Diagnosis
The diagnosis of benzodiazepine overdose may be difficult, but is usually made based on the clinical presentation of the patient along with a history of overdose. Obtaining a laboratory test for benzodiazepine blood concentrations can be useful in patients presenting with CNS depression or coma of unknown origin. Techniques available to measure blood concentrations include thin layer chromatographyThin layer chromatography
Thin layer chromatography is a chromatography technique used to separate mixtures. Thin layer chromatography is performed on a sheet of glass, plastic, or aluminum foil, which is coated with a thin layer of adsorbent material, usually silica gel, aluminium oxide, or cellulose...
, gas liquid chromatography with or without a mass spectrometer, and radioimmunoassay
Radioimmunoassay
Radioimmunoassay is a very sensitive in vitro assay technique used to measure concentrations of antigens by use of antibodies...
. Blood benzodiazepine concentrations, however, do not appear to be related to any toxicological effect or predictive of clinical outcome. Blood concentrations are, therefore, used mainly to confirm the diagnosis rather than being useful for the clinical management of the patient.
Treatment
Gastric lavage
Gastric lavage, also commonly called stomach pumping or Gastric irrigation, is the process of cleaning out the contents of the stomach. It has been used for over 200 years as a means of eliminating poisons from the stomach. Such devices are normally used on a person who has ingested a poison or...
(stomach pumping) or whole bowel irrigation
Whole bowel irrigation
Whole bowel irrigation is a medical process involving the rapid administration of large volumes of an osmotically balanced polyethylene glycol solution , either orally or via a nasogastric tube, to flush out the entire gastrointestinal tract.-History:Whole bowel irrigation was originally developed...
are also not recommended. Enhancing elimination
Clearance (medicine)
In medicine, the clearance is a measurement of the renal excretion ability. Although clearance may also involve other organs than the kidney, it is almost synonymous with renal clearance or renal plasma clearance. Each substance has a specific clearance that depends on its filtration characteristics...
of the drug with hemodialysis
Hemodialysis
In medicine, hemodialysis is a method for removing waste products such as creatinine and urea, as well as free water from the blood when the kidneys are in renal failure. Hemodialysis is one of three renal replacement therapies .Hemodialysis can be an outpatient or inpatient therapy...
, hemoperfusion
Hemoperfusion
Hemoperfusion is a medical process used to remove toxic substances from a patient's blood. The technique involves passing large volumes of blood over an adsorbent substance. The adsorbent substance most commonly used in hemoperfusion are resins and activated carbon...
, or forced diuresis
Forced diuresis
Forced diuresis may enhance the excretion of certain drugs in urine and is used to treat drug overdose or poisoning of these drugs and hemorrhagic cystitis.-Diuretics:...
is unlikely to be beneficial as these procedures have little effect on the clearance
Clearance (medicine)
In medicine, the clearance is a measurement of the renal excretion ability. Although clearance may also involve other organs than the kidney, it is almost synonymous with renal clearance or renal plasma clearance. Each substance has a specific clearance that depends on its filtration characteristics...
of benzodiazepines due to their large volume of distribution
Distribution (pharmacology)
Distribution in pharmacology is a branch of pharmacokinetics which describes the reversible transfer of drug from one location to another within the body....
and lipid solubility.
Supportive measures
Supportive measures include observation of vital signsVital signs
Vital signs are measures of various physiological statistics, often taken by health professionals, in order to assess the most basic body functions. Vital signs are an essential part of a case presentation. The act of taking vital signs normally entails recording body temperature, pulse rate ,...
, especially Glasgow Coma Scale
Glasgow Coma Scale
Glasgow Coma Scale or GCS is a neurological scale that aims to give a reliable, objective way of recording the conscious state of a person for initial as well as subsequent assessment...
and airway patency. IV access with fluid administration and maintenance of the airway with intubation
Intubation
Tracheal intubation, usually simply referred to as intubation, is the placement of a flexible plastic or rubber tube into the trachea to maintain an open airway or to serve as a conduit through which to administer certain drugs...
and artificial ventilation may be required if respiratory depression or pulmonary aspiration occurs. Supportive measures should be put in place prior to administration of any benzodiazepine antagonist in order to protect the patient from both the withdrawal effects and possible complications arising from the benzodiazepine. A determination of possible deliberate overdose should be considered with appropriate scrutiny, and precautions taken to prevent any attempt by the patient to commit further bodily harm. Hypotension is corrected with fluid replacement, although catecholamine
Catecholamine
Catecholamines are molecules that have a catechol nucleus consisting of benzene with two hydroxyl side groups and a side-chain amine. They include dopamine, as well as the "fight-or-flight" hormones adrenaline and noradrenaline released by the adrenal medulla of the adrenal glands in response to...
s such as norepinephrine
Norepinephrine
Norepinephrine is the US name for noradrenaline , a catecholamine with multiple roles including as a hormone and a neurotransmitter...
or dopamine
Dopamine
Dopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...
may be required to increase blood pressure
Blood pressure
Blood pressure is the pressure exerted by circulating blood upon the walls of blood vessels, and is one of the principal vital signs. When used without further specification, "blood pressure" usually refers to the arterial pressure of the systemic circulation. During each heartbeat, BP varies...
. Bradycardia
Bradycardia
Bradycardia , in the context of adult medicine, is the resting heart rate of under 60 beats per minute, though it is seldom symptomatic until the rate drops below 50 beat/min. It may cause cardiac arrest in some patients, because those with bradycardia may not be pumping enough oxygen to their heart...
is treated with atropine
Atropine
Atropine is a naturally occurring tropane alkaloid extracted from deadly nightshade , Jimson weed , mandrake and other plants of the family Solanaceae. It is a secondary metabolite of these plants and serves as a drug with a wide variety of effects...
or an infusion of norepinephrine to increase coronary blood flow
Blood flow
Blood flow is the continuous running of blood in the cardiovascular system.The human body is made up of several processes all carrying out various functions. We have the gastrointestinal system which aids the digestion and the absorption of food...
and heart rate
Heart rate
Heart rate is the number of heartbeats per unit of time, typically expressed as beats per minute . Heart rate can vary as the body's need to absorb oxygen and excrete carbon dioxide changes, such as during exercise or sleep....
.
Flumazenil
FlumazenilFlumazenil
Flumazenil is a benzodiazepine antagonist available for injection only, and the only benzodiazepine receptor antagonist on the market today.It was first introduced in 1987 by Hoffmann-La Roche under the trade name Anexate, but only approved by...
(Anexate) is a competitive benzodiazepine receptor antagonist
Antagonist
An antagonist is a character, group of characters, or institution, that represents the opposition against which the protagonist must contend...
that can be used as an antidote
Antidote
An antidote is a substance which can counteract a form of poisoning. The term ultimately derives from the Greek αντιδιδοναι antididonai, "given against"....
for benzodiazepine overdose. Its use, however, is controversial as it has numerous contraindications. It is contraindicated in patients who are on long-term benzodiazepines, those who have ingested a substance that lowers the seizure threshold
Seizure threshold
A seizure threshold is the balance between excitatory and inhibitory forces in the brain which affects how susceptible one is to seizures. Those diagnosed with epilepsy or certain other neurological conditions are vulnerable to sudden new seizures if the threshold is upset, and so must be...
, or in patients who have tachycardia, widened QRS complex
QRS complex
The QRS complex is a name for the combination of three of the graphical deflections seen on a typical electrocardiogram . It is usually the central and most visually obvious part of the tracing. It corresponds to the depolarization of the right and left ventricles of the human heart...
on ECG, anticholinergic
Anticholinergic
An anticholinergic agent is a substance that blocks the neurotransmitter acetylcholine in the central and the peripheral nervous system. An example of an anticholinergic is dicycloverine, and the classic example is atropine....
signs, or a history of seizures. Due to these contraindications and the possibility of it causing severe adverse effects including seizures, adverse cardiac effects, and death, in the majority of cases there is no indication for the use of flumazenil in the management of benzodiazepine overdose as the risks in general outweigh any potential benefit of administration. It also has no role in the management of an unknown overdoses. In addition, if full airway protection has been achieved, a good outcome is expected, and therefore flumazenil administration is unlikely to be required.
Flumazenil is very effective at reversing the CNS depression
CNS depression
Central nervous system depression or CNS depression refers to physiological depression of the central nervous system that can result in decreased rate of breathing, decreased heart rate, and loss of consciousness possibly leading to coma or death...
associated with benzodiazepines but is less effective at reversing respiratory depression. One study found that only 10% of the patient population presenting with a benzodiazepine overdose are suitable candidates for flumazenil. In this select population who are naive to and overdose solely on a benzodiazepine, it can be considered. Due to its short half life
Half-life
Half-life, abbreviated t½, is the period of time it takes for the amount of a substance undergoing decay to decrease by half. The name was originally used to describe a characteristic of unstable atoms , but it may apply to any quantity which follows a set-rate decay.The original term, dating to...
, the duration of action of flumazenil is usually less than 1 hour, and multiple doses may be needed. When flumazenil is indicated the risks can be reduced or avoided by slow dose titration of flumazenil. Due to risks and its many contraindications, flumazenil should be administered only after discussion with a medical toxicologist
Medical toxicology
Medical toxicology, or clinical toxicology, is a subspecialty of medicine. It is practiced by toxicologists, but toxicologic knowledge is often used in emergency medicine, occupational medicine and pediatrics...
.
Epidemiology
In a Swedish (2003) study benzodiazepines were implicated in 39% of suicides by drug poisoning in the elderly 1992-1996. NitrazepamNitrazepam
Nitrazepam is a type of benzodiazepine drug and is marketed in English-speaking countries under the following brand names: Alodorm, Arem, Insoma, Mogadon, Nitrados, Nitrazadon, Ormodon, Paxadorm, Remnos, and Somnite...
and flunitrazepam
Flunitrazepam
Flunitrazepam is marketed as a potent hypnotic, sedative, anticonvulsant, anxiolytic, amnestic, and skeletal muscle relaxant drug most commonly known as Rohypnol...
accounted for 90% of benzodiazepine implicated suicides. In cases, where benzodiazepines contributed to death, but were not the sole cause, drowning, typically in the bath, was a common method used. Benzodiazepines were the predominant drug class in suicides in this review of Swedish death certificates. In 72% of the cases, benzodiazepines were the only drug consumed. Thus, many of deaths associated with benzodiazepine overdoses may not be a direct result of the toxic effects but either due to being combined with other drugs or used as a tool to complete suicide using a different method, e.g. drowning.
In a Swedish retrospective study of deaths of 1987, in 159 of 1587 autopsy cases benzodiazepines were found. In 44 of these cases the cause of death was natural causes
Death by natural causes
A death by natural causes, as recorded by coroners and on death certificates and associated documents, is one that is primarily attributed to natural agents: usually an illness or an internal malfunction of the body. For example, a person dying from complications from influenza or a heart attack ...
or unclear. The remaining 115 deaths were due to accidents (N = 16), suicide (N = 60), drug addiction (N = 29) or alcoholism
Alcoholism
Alcoholism is a broad term for problems with alcohol, and is generally used to mean compulsive and uncontrolled consumption of alcoholic beverages, usually to the detriment of the drinker's health, personal relationships, and social standing...
(N = 10). In a comparison of suicides and natural deaths, the concentrations both of flunitrazepam and nitrazepam (sleeping medications) were significantly higher among the suicides.
In four cases benzodiazepines were the sole cause of death.
In Australia, a study of 16 deaths associated with toxic concentrations of benzodiazepines during the period of 5 years leading up to July 1994 found preexisting natural disease as a feature of 11 cases; 14 cases were suicides. Cases where other drugs, including ethanol, had contributed to the death were excluded. In the remaining five cases, death was caused solely by benzodiazepines. Nitrazepam and temazepam were the most prevalent drugs detected, followed by oxazepam and flunitrazepam. A review of self poisonings of 12 months 1976 - 1977 in Auckland
Auckland
The Auckland metropolitan area , in the North Island of New Zealand, is the largest and most populous urban area in the country with residents, percent of the country's population. Auckland also has the largest Polynesian population of any city in the world...
, New Zealand
New Zealand
New Zealand is an island country in the south-western Pacific Ocean comprising two main landmasses and numerous smaller islands. The country is situated some east of Australia across the Tasman Sea, and roughly south of the Pacific island nations of New Caledonia, Fiji, and Tonga...
, found benzodiazepines implicated in 40% of the cases. A 1993 British study found flurazepam and temazepam to have the highest number of deaths per million prescriptions among medications commonly prescribed in the 1980s. Flurazepam, now rarely prescribed in the United Kingdom and Australia, had the highest fatal toxicity index of any benzodiazepine (15.0) followed by Temazepam (11.9), versus 5.9 for benzodiazepines overall, taken with or without alcohol.