Practice Essentials
Overdoses involving oral benzodiazepines (BZDs) alone rarely result in significant morbidity (eg, aspiration pneumonia, rhabdomyolysis) or mortality. Serious adverse effects and emergency department visits related to BZD overdose usually involve concomitant ingestions of other agents. [1] In mixed overdoses, BZDs can potentiate the effect of alcohol or other sedative-hypnotics. Intravenous administration of BZDs is associated with greater degrees of respiratory depression. [2]
Prolonged parenteral administration of BZDs places patients at risk for propylene glycol poisoning (the diluent used in parenteral formulations of diazepam and lorazepam). Rapid infusions of propylene glycol can induce hypotension. Accumulated propylene glycol can lead to anion gap metabolic acidosis, lactic acidosis, and hyperosmolarity. Rarely, propylene glycol toxicity may result in cardiac arrhythmias, seizures, or coma. [3, 4]
In long-term users who have developed dependence, cessation of BZDs can result in a withdrawal syndrome, with manifestations including anxiety, irritability, confusion, seizures, and sleep disorders. [5] Alprazolam (Xanax) withdrawal syndrome may be especially severe, with associated delirium, psychosis, and hyperadrenergic states. [6] Treatment of BZD withdrawal is typically with a long-acting BZD (eg, clonazepam), but successful use of antiseizure drugs (eg, valproate, carbamazepine) has also been reported. [6]
In 2020, the US Food and Drug Administration (FDA) updated the required boxed warnings and package inserts for all BZDs to include information on the potential for abuse, addiction, and other serious risks.
Background
Benzodiazepine (BZD) toxicity may result from accidental overdose, intentional overdose, or recreational abuse. Since their introduction in 1960, BZDs have become indicated for a variety of conditions, including seizures, anxiety, alcohol withdrawal, insomnia, agitation, and muscle spasm. In addition, BZDs are used as preanesthetic agents, and are frequently combined with other medications, such as opioids, for procedural sedation. BZD overdose often occurs in association with other substances. [11]
Pathophysiology
Benzodiazepines (BZDs) act by potentiating the activity of gamma-aminobutyric acid (GABA), which is the major inhibitory neurotransmitter in the central nervous system (CNS). BZDs bind to a specific receptor on the GABA A receptor complex and thereby facilitate the binding of GABA to its specific receptor site. BZD binding causes increased frequency of opening of the chloride channel complexed with the GABA A receptor. Chloride channel opening results in membrane hyperpolarization, which inhibits cellular excitation.
Enhanced GABA neurotransmission results in sedation, striated muscle relaxation, anxiolysis, and anticonvulsant effects. Stimulation of GABA receptors within the peripheral nervous system (PNS) may cause decreased cardiac contractility and vasodilation. These changes could be detrimental to adequate tissue perfusion.
The rate of BZD onset of action is determined by its ability to cross the blood-brain barrier. The relatively lipophilic BZDs (eg, diazepam) usually have a faster onset of effect than the relatively water-soluble BZDs (eg, lorazepam). BZD effects can be potentiated when ethanol is also present. Regardless of the specific BZD, most agents will reach peak blood concentrations within 1-3 hours.
After a single dose, the lipophilic agents can have a shorter duration of action (shorter CNS effect) than water-soluble agents due to rapid redistribution from the CNS to peripheral sites (eg, adipose tissue); thus, lorazepam has a longer CNS duration of action than diazepam. However, diazepam is metabolized to active intermediates with prolonged half-lives, which extend the parent drug's therapeutic effects.
BZDs are metabolized predominantly in the liver by oxidation and/or conjugation. Most BZDs are broken down into pharmacologically active metabolites, which may have longer half-lives than the parent compounds.
Epidemiology
According to the Drug Abuse Warning Network (DAWN) of the Substance Abuse and Mental Health Services Administration (SAMHSA), total emergency department (ED) visits for nonmedical use of benzodiazepines (BZDs) rose 149% from 2004 to 2011. However, no short-term increases were noted between 2009 and 2011. Records did not always specify the BZD involved, but alprazolam was indicated in about a third of these ED visits and in approximately a third of BZD-related suicide attempts. [12]
DAWN was discontinued in 2011. In 2018, SAMHSA reinstated DAWN. The 2022 DAWN report notes that the rate of BZD-related ED visits was highest in individuals age 26 to 44 years (98 per 100,000). Rates of BZD-related ED visits were similar in males and females (54 per 100,000 and 60 per 100,000, respectively). [13]
From 1996 to 2013, the percentage of US adults filling a BZD prescription increased 67%, from 8.1 million to 13.5 million, and the median cumulative quantity of BZD prescriptions filled over the year increased by 140%. The overdose death rate increased from 0.58 to 3.07 per 100,000 adults, with a plateau seen after 2010, although deaths continued to increase in the elderly and in Blacks and Hispanics. In 2013, BZDs accounted for approximately 31% of fatal overdoses involving prescription drugs in the US. However, the danger of BZDs may be obscured by the fact that an estimated 75% of deaths involving BZDs also involve an opioid. [14]
From 2010 to 2017, annual BZD-associated deaths in the US increased 8.9-fold to 11,537. [15]
In 2022, a total of 15,911 single-substance exposures to BZDs were reported to US poison control centers. Of these, 701 (4%) resulted in major toxicity and 17 resulted in death. [16] Inclusion of cases involving BZDs in combination with alcohol or other drugs yields much higher numbers. DAWN reported that BZDs were involved in 123,572 of the 606,653 ED visits in 2011 that involved drugs and alcohol taken together (20.4%). [12]
The majority of reported BZD toxicity cases are in persons older than 19 years. [16] However, the elderly and the very young are more susceptible to the CNS depressant effects of BZDs compared with people in other age groups.
In Ontario, Canada between 2013 and 2020, the overall incidence of BZD toxicity declined from 28.0 to 26.1 per 100,000 but increased over 60% among young adults 19-24 years old (39.9 to 66.6 per 100,000). Additionally, in 2020 less than 50% of toxic incidents were associated with prescribed BZDs and nearly 29% involved multiple substances (eg, opioid, stimulant, or alcohol). [17]
Prognosis
Oral benzodiazepine (BZD) overdoses, without co-ingestions, rarely result in significant morbidity (eg, aspiration pneumonia, rhabdomyolysis) or mortality. Polypharmacy overdoses involving BZDs and other agents can result in more severe toxicity. Alcohol or other sedative-hypnotics in particular can potentiate the effects of BZDs.
Individuals with opioid dependence commonly misuse BZDs, to self-medicate and/or to increase the effects of opioids. [18] Although BZDs taken alone are generally well tolerated in overdose, it has been suggested that the combination of BZDs and opioid analgesics can increase the risk of respiratory depression. [19] In particular, the combination of alprazolam with opioids may be fatal. Analysis of a West Virginia forensic database showed that alprazolam contributed to 17% of drug-related deaths. At least one other drug—typically an opioid, but also another BZD in some patients—was identified in 97.5% of the alprazolam cases. [20]
Overdose of ultrashort-acting BZDs (eg, triazolam [Halcion]) is more likely to result in apnea and death than overdose with longer-acting BZDs. Of individual BZDs, alprazolam is relatively more toxic than others in overdose. [21] During 2003 to 2009, death rates from alprazolam increased 233.8%; alprazolam was second only to oxycodone among prescription drugs with the highest increase in death rates. [22]
Similarly, an Australian study reported that alprazolam-positive cases of sudden or unnatural death increased from three cases in 1997 to 86 cases in 2012. The increase was driven mostly by accidental toxicity in people with known drug or alcohol dependence. Drugs other than alprazolam and its metabolites were present in 94.9% of cases. The most commonly detected drugs, in order of decreasing frequency, were opioids, other BZDs, and alcohol. [23]
The 2023 European Drug Report noted that although data were limited, BZDs are linked to increasing risk of death when mixed with synthetic opioids. [24]
