Jasmine Carpenter is a Mental Health Clinical Pharmacy Specialist; Tiffany Lee is a Geriatric Clinical Pharmacy Specialist; and Elizabeth Green is a Women’s Clinic Psychiatrist; all at the Washington Veterans Affairs Medical Center in the District of Columbia. Eileen Holovac is an Oncology Clinical Pharmacy Specialist at the Palo Alto Veterans Affairs Medical Center in California. Correspondence: Jasmine Carpenter (jasmine.carpenter@va.gov)
Author disclosures The authors report no actual or potential conflicts of interest with regard to this article.
Disclaimer The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the US Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review the complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.
In 2018 there were 834 fatalities from 174,269 single-substance exposure to analgesics, which include opioids and acetaminophen, for a mortality rate of 0.5%.16 The opioid epidemic is one of the main drivers of the increase in drug overdose deaths in the US.16,17 The opioid with the highest drug overdose fatality rate is illicitly manufactured fentanyl, which often is combined with other substances, such as heroin, to increase its potency at a low cost.18 These combinations also increase the risk of overdose fatality.
Acetaminophen is unique among the top substances associated with fatalities because it is obtained easily without a prescription. An acetaminophen overdose can cause hepatic injury, which may progress to fulminant hepatic failure and death.19 The recommended maximum dose of acetaminophen is 4 g/d in an adult and 50 to 75 mg/kg/d in children. A single acute ingestion of > 7.5 g in an adult or 150 mg/kg in children has been considered potentially toxic.19,20 The use of combination analgesics that contain both an opioid and acetaminophen can pose an even greater risk due to the potential for respiratory depression and hepatotoxicity.
Cardiovascular drugs accounted for 232 fatalities from 46,499 single-substance exposures (mortality rate: 0.5%).16 According to the AAPCC, calcium channel blockers (CCB) and β-blockers accounted for 63% of overdose deaths by cardiovascular drugs because they can cause severe hypotension, bradycardia, and hemodynamic collapse.16,21,22
In the past, the nondihydropyridine CCBs verapamil and diltiazem were associated with increased overdose fatalities. However, the most recent data show that dihydropyridine CCBs such as amlodipine also have significant risk for lethality.16 Metoprolol was associated with more overdose deaths in the past year among β-blockers. However, caution also should be used with agents such as propranolol and labetalol, which can antagonize sodium channels in overdose and may be associated with a higher risk of mortality than other β-blockers.22
Antidepressants accounted for 144 fatalities from 56,891 single-substance exposures (mortality rate: 0.3%).16 Nelson and Spyker performed a study to determine the morbidity and mortality index for psychotropic agents based on exposure reports from the National Poison Data system and found that tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs) had the highest morbidity and mortality rates among all drugs used to treat depression.23 As a class, TCAs have a mortality index of 40.7 per 10,000 exposures and are associated with higher rates of acidosis, cardiac conduction problems, respiratory depression, and seizures (Table 2).23 Amitriptyline accounted for 39.5% of deaths from antidepressants.23 Among newer antidepressants, citalopram, venlafaxine, and bupropion have been found to be the most hazardous.23 Citalopram and venlafaxine have morbidity indices that are 4- to 5-fold higher than sertraline. Adverse events associated with bupropion, venlafaxine, and citalopram, such as seizures, conduction disturbances, hallucinations, and tachycardia contribute to the morbidity and mortality related to these medications (Table 3).
Of the atypical antipsychotics, olanzapine, quetiapine, and ziprasidone have the highest mortality rates.23 Cardiac conduction problems were more frequent with olanzapine and ziprasidone, and respiratory depression was more frequent with olanzapine and quetiapine. Aripiprazole had the lowest rates of morbidity and mortality.23
Of the mood stabilizers, lithium, valproic acid, and carbamazepine have narrow therapeutic indices and, therefore, moderately high mortality rates.23 Lithium was associated with higher rates of bradycardia, confusion, and renal problems. Valproic acid had relatively high levels of acidosis and coma. Carbamazepine had high rates of coma and the highest rate of nystagmus.
Sedatives and hypnotics accounted for 97 fatalities of 51,495 single-substance exposures (mortality rate 0.2%).16 Within this category, benzodiazepines (BZDs), particularly alprazolam, clonazepam, and diazepam, were associated with the highest number of overdose deaths.16 Although fatalities from single-substance exposure to this category are low, it should be noted that BZDs are primarily metabolized by the CYP2C19 and CYP3A4 enzymes. Interactions with other drugs also metabolized by the same CYP enzymes may lead to prolonged effects of BZDs, such as sedation, and respiratory depression, which significantly increase the risk of overdose death. Furthermore, lipophilic BZDs, such as diazepam, can accumulate in the tissue after multiple doses and have impaired clearance in older patients.
