[NOTE: This article has been posted prior to peer review for use in an active research program. This content will be updated with a peer reviewed version as soon as it is available.]
Hypersensitivity
Some patients may exhibit an allergic reaction to benzodiazepines, including rash, hives, angioedema, and anaphylaxis.1-8 Manufacturers advise that patients with a known history of hypersensitivity to benzodiazepines or any of their inactive ingredients should avoid the use of benzodiazepines. Hypersensitivity to benzodiazepines has only been reported in case studies, so the exact incidence is difficult to estimate.
Abuse Potential
Benzodiazepines can be abused, leading to the risk of overdose or even death.1-8 A cross-sectional analysis of data from the 2015 and 2016 National Survey on Drug Use and Health (NSDUH) estimated that 2.2% of adults misused benzodiazepines, accounting for 17.2% of all benzodiazepine use.9 Manufacturers advise that abuse potential increases with concomitant use of certain medications (e.g., opioid analgesics, stimulants), alcohol, and/or illicit substances. They further advise screening patients for abuse potential before prescribing benzodiazepines and counseling patients on the risks and proper use of benzodiazepines.
Although benzodiazepine use is common, overdose is uncommon. An analysis of 2019-2020 data from the National Syndromic Surveillance Program and the Center for Disease Control and Prevention’s (CDC) Overdoes Data to Action (OD2A) program estimated the incidence of nonfatal and fatal overdoes associated with benzodiazepines.10 Out of 17 million emergency department visits, 31,377 involved nonfatal benzodiazepine overdose over the two years (estimated prevalence of 0.09% each year). Out of 41,496 overdoes deaths reported between 2019-2020, benzodiazepines without concomitant use of opioids were only involved in 598 (1.4%).
Somnolence and Sedation
Because of benzodiazepines depress the central nervous system, they can lead to somnolence or sedation.1-8 Manufacturers advise that patients avoid engaging in hazardous occupations or activities requiring complete mental alertness such as operating machinery or driving a motor vehicle. They further recommend counseling patients on the compounding effects on somnolence and sedation with concomitant use of benzodiazepines with other central nervous system depressants such as alcohol.
Concomitant Use with Opioids
Manufacturers warn that concomitant use of benzodiazepines and opioids can result in profound sedation, respiratory depression, coma, and even death.1-8 Manufacturers advise avoiding concomitant use, or if absolutely necessary, reserving concomitant use for patients for whom there are not adequate alternative treatment options and prescribing the lowest effective dosage and minimum duration of concomitant use. They further advise following any patients using opioids and benzodiazepines concomitantly closely for signs and symptoms of respiratory depression and sedation.
Dependence and Withdrawal
Continued use of benzodiazepines can lead to physical dependence which can in turn result in withdrawal symptoms, particularly with abrupt discontinuation.1-8 Acute withdrawal symptoms include abnormal involuntary movements, anxiety, depersonalization, depression, derealization, dizziness, fatigue,
gastrointestinal adverse reactions (e.g., nausea, vomiting, diarrhea, weight loss, decreased appetite), headache, hypertension, irritability, insomnia, memory impairment, muscle pain and stiffness, panic attacks, restlessness, sensory disturbances (e.g., auditory and visual hallucinations, blurred vision, hyperacusis, photophobia), tachycardia, and tremor. More severe withdrawal signs and symptoms, including life-threatening reactions, have included catatonia, convulsions, delirium tremens, hallucinations, mania, psychosis, seizures, and suicidality.
Severe withdrawal symptoms are very rare making it difficult to estimate incidence. An analysis of one hospital’s electronic records found that from 2009-2016, there were 82 reports of benzodiazepine withdrawal.11 Of these cases, 31 involved concurrent withdrawal from another drug (25 opioid, six ethanol). Among these cases, seven were admitted to the intensive care unit, although only two of these were withdrawing from benzodiazepines alone. Seizures occurred in eight cases.
Protracted withdrawal symptoms lasting weeks to over a year have been reported with symptoms including anxiety, cognitive impairment, depression, insomnia, formication, motor symptoms (e.g., weakness, tremor, muscle twitches), paresthesia, and tinnitus.1-8 However, because of the length that these symptoms have been reported to last, it’s difficult to know whether they are truly a result of withdrawal or potentially the re-emergence of symptoms the medication had been introduced to treat.
Manufacturers recommend that when discontinuing a benzodiazepine, patients gradually reduce their dose if possible to reduce the risk of adverse effects.1-8
Depression
Benzodiazepines may worsen depression.1-8 Additionally, episodes of hypomania and mania have been reported in association with the use of benzodiazepines in patients with depression. Manufacturers advise taking appropriate precautions in patients with depression, such as limiting the total prescription size and increased monitoring for suicidal ideation.
Suicidal Ideation
Benzodiazepines have been associated with increased incidence of suicidal thoughts and behaviors.1-8 In a large placebo-controlled trail (n=43,892), the estimated incidence rate of suicidal behavior or ideation was 0.43% among those taking a benzodiazepine compared to 0.24% in the placebo arm. Manufacturers recommend that patients be monitored for emergence or suicidal ideation or any unusual changes in mood or behavior.
Neonatal Sedation and Withdrawal Syndrome
Benzodiazepine use late in pregnancy can result in sedation and/or withdrawal symptoms in the fetus.1-8 These effects may be dangerous to the fetus, especially sedation which can lead to respiratory depression, lethargy, or hypotonia. Manufacturers recommend monitoring any fetuses exposed to benzodiazepines during pregnancy or labor for signs of sedation or withdrawal.
Risk in Patients with Impaired Respiratory Function
There have been reports of death in patients with severe pulmonary disease after the initiation benzodiazepines.1-8 Manufacturers advise closely monitoring patients with impaired respiratory function and discontinuing use of benzodiazepines if there are any signs and symptoms of respiratory depression, hypoventilation, or apnea.
Concomitant Use with Cytochrome P450 3A Inhibitors
Due to the mechanism of action for benzodiazepines, concomitant use with cytochrome P450 3A (CYP3A) inhibitor drugs (e.g., cimetidine, ketoconazole, fluvoxamine, fluoxetine, omeprazole, ritonavir, nefazodone) can increase plasma benzodiazepine concentrations.1-8 Manufacturers recommend that concomitant use of CYP31 inhibitor and benzodiazepines be done with caution, making sure to properly adjust the dosage of benzodiazepines as is appropriate.
References
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- Onfi (clobazam) tablets [package insert]. Winchester, KY: Catalent Pharma Solution; 2024.
- Klonopin (clonazepam) tablets [package insert]. Montgomery, AL: H2-Pharma; 2023.
- Valium (diazepam) tablets [package insert]. Wixom, MI: Waylis Therapeutics; 2023.
- Ativan (lorazepam) tablets [package insert]. Bridgewater, NJ: Bausch Health; 2023.
- Doral (quazepam) tablets [package insert]. Atlanta, GA: Galt Pharmaceuticals; 2023.
- Restoril (temazepam) tablets [package insert]. Webster Groves, MO: SpecGx; 2023.
- Halcion (triazolam) tablets [package insert]. New York, NY: Pharmacia & Upjohn Co; 2023.
- Maust DT, Lin LA, Blow FC. Benzodiazepine Use and Misuse Among Adults in the United States. Psychiatr Serv. Feb 1 2019;70(2):97-106. doi:10.1176/appi.ps.201800321
- Liu S, O'Donnell J, Gladden RM, McGlone L, Chowdhury F. Trends in Nonfatal and Fatal Overdoses Involving Benzodiazepines - 38 States and the District of Columbia, 2019-2020. MMWR Morb Mortal Wkly Rep. Aug 27 2021;70(34):1136-1141. doi:10.15585/mmwr.mm7034a2
- Thornton SL, Whitacre J, Pallo N, Roberts N, Oller L. A Retrospective Review of Morbidity and Mortality Associated with Acute Benzodiazepine Withdrawal at a Midwestern Academic Medical Center. Kans J Med. 2021;14:77-79. doi:10.17161/kjm.vol1414653
