This critical review will explore the use of antidotes for drug toxicity in prehospital care, focusing on flumazenil as a treatment for benzodiazepine poisoning. It will detail the potential for practice development for the role of the ambulance-based paramedic.
Drug overdose (including both accidental and suicidal), drug interactions and drug toxicity secondary to incorrect drug doses can all result in toxicological emergencies, which put ever-increasing demands on the hospital and prehospital settings (Chacko and Peter, 2019).
While in-hospital mortality rates are <0.5% in acutely poisoned patients, a further 5% of patients have other serious clinical outcomes (Kuang et al, 2009). In some cases, appropriate and timely use of an antagonist or antidote can terminate the progression of toxicity; evidence suggests that administration of a specific antidote combined with general supportive care can reduce rates of morbidity and mortality related to life-threatening poisonings (Pillay, 2008). Chacko and Peter (2019) note that, conversely, inappropriate use or delayed administration may result in adverse patient outcomes.
The principal focus should be on ensuring adequate airway, breathing and circulation and the use of an antidote should not interfere with this (Chacko and Peter, 2019).
Kuang et al (2009) state that correct management of poisoning requires an adequate understanding of the pathophysiology and toxicokinetics of the ingested compound, alongside knowledge of how to safely remove it from the body. However, research is lacking in this area and there is limited evidence-based information available. Methods for managing poisoning need to be studied through randomised controlled trials to identify which are most effective (Kuang et al, 2009).
Antidotes
Chacko and Peter (2019) define antidotes as agents that reverse the effects of poisons on the body. Their mode of action is achieved by enzyme inhibition, binding to and neutralising a poison, thereby inhibiting absorption and mitigating end-organ damage, or through prevention of metabolism of the poison (Chacko and Peter, 2019).
Adverse symptoms associated with exposure to exogenous agents such as metals, drugs and toxins can be managed by specific antidotes; although these medications can improve patient outcomes, prevention remains the unsurpassed solution (Wang and Kazzi, 2012).
While antidotes can play a vital role in the management of poisoning, they must be administered within the correct time frame to ensure effectiveness. Some poisons require immediate antidotes while others allow the clinician more time. However, antidotes are often not supplied sufficiently to clinicians whose patients may benefit from them (Dart et al, 2009). Such practitioners include to ambulance-based paramedics, who are often the first point of care for a patient with severe or life-threatening poisoning. A limited number of antidotes that are used systematically in the management of patients with poisoning are available; these focus primarily on the reversal of paracetamol (acetaminophen), opioid and benzodiazepine toxicity (Kuang et al, 2009).
Acetylcysteine is an effective antidote used in the treatment of paracetamol toxicity. If administered within an appropriate time frame after a paracetamol overdose, it can reduce the severity and risk of acute liver injury (Waring, 2012). Naloxone hydrochloride is a valuable diagnostic and therapeutic drug indicated for opioid poisoning, and is effective in reversing respiratory and cardiovascular depression resulting from opioid toxicity (Handal et al, 1983).
Another well-used drug that could be considered an antidote is activated charcoal, which is valuable in treating a variety of agents in poisoning, particularly if administered within 1 hour of ingestion (National Institute for Health and Care Excellence (NICE), 2023). NICE (2023) continues to state that activated charcoal is effective in the prevention of absorption of poisons as it binds to a variety of agents while in the gastrointestinal system, thereby improving patient outcomes.
NICE (2021a) indicates the use of activated charcoal for benzodiazepine poisoning provided that the patient is alert and their airway is patent. However, in many cases of moderate to severe benzodiazepine poisoning, airway and breathing can be compromised. In patients who are experiencing respiratory depression, flumazenil can prevent the need for ventilation (Seelhammer et al, 2018).
Flumazenil
Flumazenil is indicated by NICE (2021a) guidelines to reverse the sedative effects of benzodiazepines and should be administered by clinicians knowledgeable in its use. Flumazenil is an imidazobenzodiazepine, which was first synthesised in 1979 by Hoffmann-La Roche (Sivilotti, 2016).
It is a benzodiazepine antagonist, which competes at the benzodiazepine binding site in the central nervous system; it is currently the only drug clinically approved for benzodiazepine poisoning as it reverses its central nervous system effects (Baandrup et al, 2018). It is also known to reverse the binding of benzodiazepines to benzodiazepine receptors, so is an example of an agonist (Sharbaf Shoaf et al, 2022).
However, multiple doses are often required because it has a short half-life (Davies, 2007). This antidote has a rapid onset time of around 1–2 minutes and peaks at 6–10 minutes following administration. Duration depends on dose and benzodiazepine plasma concentrations, and is approximately 19–50 minutes (Sharbaf Shoar et al, 2022). The rapid onset and short half-life make it an ideal candidate for ambulance-based practice.
Flumazenil intravenous injections are commonly used in clinical procedures and anaesthesia as the drug has the capability to perform partial or total reversal of the of benzodiazepines that are often used in sedation (Baandrup et al, 2018). Additionally, it is known to speed recovery times following surgery and minor clinical procedures and is popular in dentistry as it reduces postoperative monitoring periods, resulting in faster patient discharge times (Seelhammer et al, 2018).
Clearly, these uses are not needed within the ambulance-based paramedic scope of practice, but flumazenil is beneficial in reversing coma resulting from a benzodiazepine overdose (Seelhammer et al, 2018).
Because of a significant increase in demand for prescription-originated benzodiazepines, there has been a substantial rise in abuse of this drug and this problem has reached epidemic levels in the United States (Schmitz, 2016). However, Wise (2016) points out that epidemic levels of prescription drug misuse are no longer limited to the United States and that this epidemic is extending to the UK, which has one of the highest rates of prescription drug use throughout Europe (Wise, 2016). While prescription drug misuse has been brought to attention in recent years and visits to emergency departments and associated deaths have soared, there is still little known about benzodiazepine misuse (Olfson et al, 2015). Considering this substantial increase of misuse in today's society, a benzodiazepine antidote could be the next thing required within ambulance services.
Presently the cost of flumazenil in the UK is in the range if £65.50–£140 for 100 μg/1 ml, making it a costly drug in comparison to naloxone, which is currently marketed at around £36.72–£49 per 400 μg/1 ml solution. In the UK, opioid-related deaths in 2020 surmounted a total of 2263, decreasing by 1.9% to 2219 in 2021; however, benzodiazepine mortality rates soared between those years increasing by 176% with 62 deaths in 2020 compared with 171 deaths in 2021 (Office for National Statistics (ONS), 2022). Despite a significant difference in price between these two antidotes, recent census data suggests a rapidly increasing mortality rate associated with benzodiazepines (ONS, 2022). Therefore, it can be argued that, if flumazenil is administered appropriately in time-critical or life-threatening cases, cost should not stand in the way of a treatment that has a rapidly increasing relevance (Moon et al, 2020).
Multi-drug poisoning
Benzodiazepine toxicity can cause ataxia, drowsiness, dysarthria, nystagmus, respiratory depression and coma and, if a benzodiazepine is taken along with other nervous system depressants it can potentiate their effects (NICE, 2021a). Without appropriate treatment, benzodiazepines have been known to cause death (Schmitz, 2016).
While flumazenil can have a profound effect as an antidote to benzodiazepine toxicity, it is less effective in reversing sedation or coma in patients who present with multiple-drug poisoning (Sharbaf Shoar et al, 2022). This would need to be considered if flumazenil is implemented into ambulance-based practice as many drug overdose patients who require an ambulance have taken a cocktail of drugs.
An advantage of flumazenil is that it has no pharmacokinetic interaction with ethanol (Association of Ambulance Chief Executives, 2021). This is useful as intentional pharmaceutical overdoses often involve drugs being mixed with alcohol, so flumazenil treatment is potentially suitable for patients who have consumed both benzodiazepines and alcohol. Koski et al (2002) discuss that, when taken alone, benzodiazepines are often considered to be a reasonably safe drug but are frequently found to have been combined with ethanol in forensic toxicological cases.
Schmitz (2016) reports that intentional drug overdoses are commonly combined with alcohol. Therefore, flumazenil would be useful in ambulance-based paramedic practice in cases involving benzodiazepine toxicity and ethanol consumption. Schmitz (2016) also highlights that benzodiazepine misuse is commonly combined with alcohol and/or opioid use, generally resulting in poor outcomes.
Flumazenil and non-benzodiazepines
Studies have also suggested that flumazenil can reverse the effects of non-benzodiazepines.
The imidazopyridine zolpidem, the cyclopyrrolone zopiclone and the pyrazolopyrimidine zaleplon are sedatives that are structurally unlike benzodiazepines but bind to the benzodiazepine binding site and all respond effectively to these antidotes (Sivilotti, 2016).
Etizolam is another drug that is structurally dissimilar to benzodiazepines but possesses pharmacologically similar properties of hypnotic and sedative effects and is rapidly and completely reversed by flumazenil (O'Connell et al, 2015).
Limitations on use and side-effects
Flumazenil should be given exclusively for therapeutic use and not used as a diagnostic tool to determine the causative agent in a similar way to naloxone (McMenamin, 2012). McMenamin (2012) argues that many clinicians use naloxone diagnostically to determine if opioids are the cause of an altered mental state as it is presumed to be relatively innocuous drug. However, NICE (2021b) documents that naloxone can cause side effects including arrhythmias, pulmonary oedema and cardiac arrest. Conley et al (2023) investigated a case study evidencing that while naloxone may be considered relatively safe, it also poses the potential hazard that side-effects may not be recognised or potentially misattributed to other causes which can cloud judgements around diagnosis. Therefore, education and an understanding around the appropriate use of antidotes and their potential for adverse effects is required.
As with many pharmaceutical solutions, flumazenil has fundamental disadvantages. While seizures are usually an uncommon side effect (more so in patients with epilepsy), it can potentiate seizures in those in whom this neurological activity is being suppressed by benzodiazepines (NICE, 2021a). This perhaps explains why it is not commonly used in current ambulance-based paramedic practice.
Seizures are more common in long-term benzodiazepine users and in severe tricyclic antidepressant toxicity; flumazenil should be administered with caution in patients prescribed on a benzodiazepine for the management of seizures (Spivey, 1992). Clinicians should consider this when administering this antidote and carefully titrate to effect to avoid the possibility of seizures at all costs, particularly as there is no specific antidote for flumazenil (Wallace et al, 2017).
Reported cases of flumazenil overdose are rare and would not be expected in patients who are not chronic benzodiazepine users, as these patients experience benzodiazepine withdrawals suddenly following cessation of the drug (Wallace et al, 2017).
Other drawbacks of flumazenil are that it is incapable of reversing the effects of other gamma-aminobutyric acid (GABA)-ergic sedatives and hypnotics such as inhaled anaesthetics, barbiturates, propofol or ethanol, and it is incapable of treating opioid poisoning (Sivilotti, 2016). Considering the commonality of polypharmacy abuse, it could potentially be difficult to ascertain whether flumazenil would be indicated in cases where there was scepticism around the ingested agents and, as previously mentioned, it should not be used as a diagnostic tool.
Future use: hepatic encephalopathy
Research is investigating the viability of flumazenil as a therapy for hepatic encephalopathy. Some symptoms of hepatic encephalopathy, such as confusion, altered mental state and comatose-like state, are partially caused by an upregulation of GABA receptors (as with benzodiazepines), which makes flumazenil an intuitive choice of treatment (Reinert and Burnham, 2021).
In the author's experience, alcoholism and, consequently, hepatic encephalopathy are commonly seen within ambulance-based paramedic practice. Therefore, with further research, flumazenil could become more valuable within this role in future.
Conclusion
It is difficult to draw up a protocol for the management of patients with poisoning because of the variety of agents involved, their effects and antidotes available.
When considering the use of an antidote within prehospital care, the benefits of an antidote must be weighed against its possible side effects (Chacko and Peter, 2019).
Flumazenil is an antidote that has a variety of indicated and potential future uses for the ambulance-based paramedic. However, it should not replace basic airway management and current strategies of resuscitation and supportive care (Sivilotti, 2016).
Prescription drug misuse is a growing issue. When considering the development of ambulance-based paramedic practice, it is imperative to study current and future social affairs. Rates of drug misuse with associated morbidity and mortality continue to soar and current efforts to manage this epidemic have been unsuccessful (Schmitz, 2016).
Further research is required to have advanced knowledge around the risk factors for benzodiazepine abuse and what therapies can be offered in prehospital care.