Benzodiazepine overdose

Benzodiazepine overdose describes the ingestion of one of the drugs in the benzodiazepine class in quantities greater than are recommended or generally practiced. When taken alone in overdose they rarely cause severe complications or fatality, and deaths after hospital admission are rare. However, combinations of high doses of benzodiazepines with alcohol, barbiturates, opiates 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. Worldwide benzodiazepines are commonly used in overdose situations.

Background
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, with oxazepam being least toxic and least sedative and alprazolam, flunitrazepam and temazepam the most toxic and most sedative in overdose. Temazepam is more frequently involved in drug-related deaths causing more deaths per million than other benzodiazepines. However, in countries where alprazolam is commonly prescribed, alprazolam is found to be the most dangerous in overdose, causing more fatalities, higher rates of admission to ICU and higher rates of mechanical ventilation. Zopiclone, a benzodiazepine receptor agonist has similar overdose potential as benzodiazepines.

Toxicity
Benzodiazepines have a wide therapeutic index and taken alone in overdose rarely cause severe complications or fatalities. They are, however, not devoid of serious toxicity and case of severe coma or fatality have been reported. Taken in overdose in combination with alcohol, barbiturates, opiates, tricyclic antidepressants, or sedating antipsychotics, anticonvulsants, or antihistamines are particularly dangerous. In the case of alcohol and barbiturates not only do they have an additive effect, 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. Additionally, 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.

Signs and symptoms
Following an acute 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, hallucinations, 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 opiates or ethanol. The duration of symptoms following overdose is usually between 12 and 36 hours in the majority of cases.

Pathophysiology
Benzodiazepines act by enhancing the effect of the neurotransmitter gamma-aminobutyric acid (GABA), they act by binding to a specific benzodiazepine receptor 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.

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 levels can be useful in patients presenting with CNS depression or coma of unknown origin. Techniques available to measure blood concentrations include thin layer chromatography, gas liquid chromatography with or without a mass spectrometer, and radioimmunoassay. Although blood benzodiazepine levels do not appear to be related to any toxicological effect or predictive of clinical outcome. Blood levels are therefore mainly used to confirm the diagnosis rather than being useful for the clinical managemnet of the patient.

Treatment
Medical observation and supportive care are the mainstay of treatment of benzodiazepine overdose. Although benzodiazepines are adsorbed 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 proceedure. It is only recommended if benzodiazepines have been taken in combination with other drugs that may benefit from decontamination. Gastric lavage (stomach pumping) or whole bowel irrigation are similarly 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.

Supportive measures
Supportive measures include observation of vital signs, especially Glasgow Coma Scale and airway patency. IV access with fluid administration and maintenence of the airway with intubation and artifical 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 catecholamines 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.

Flumazenil
Flumazenil (Anexate) can be used as an antidote for benzodiazepines. It is a competitive benzodiazepine receptor antagonist whose use is controversial. Numerous contraindications to its use exist. 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 its many contraindications and possibility of 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 generally outweigh any potential benefit of administraion. It also has no role in the managemnt of an unknown overdoses. Additionally, 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. Due to risks and its many contraindications, flumazenil should only be administered after discussion with a toxicologist.

Epidemiology
Benzodiazepines were implicated in 39% of suicides by drug poisoning in Sweden, with nitrazepam and flunitrazepam accounting for 90% of benzodiazepine implicated suicides, in the elderly over a period of 2 decades. In three quarters of cases death was due to drowning, typically in the bath. 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 due to being combined with either 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 temazepam to have the highest number of deaths per million prescriptions among medications commonly prescribed in the 1980s (11.9, versus 5.9 for benzodiazepines overall, taken with or without alcohol).