Benzodiazepine

Benzodiazepines are a class of psychoactive drugs that consist of two ring components, namely a six-carbon benzene ring and a seven-membered heterocyclic compound that includes two nitrogen atoms. One of the first benzodiazepines that was developed is chlordiazepoxide (trade name Librium), which was formulated in the 1950s and released on the market in 1960. By the year 1963, another formulation, benzodiazepine diazepam (trade name Valium), was released. By the late 1970s, benzodiazepines were recognized as the most prescribed drug around the world.

Benzodiazepines are drugs that enhance the effect of gamma-aminobutyric acid (GABA), which is a chemical released at the ends of nerve fibers, also known as a neurotransmitter. These drugs induce sleep (hypnosis), sedation, and muscle relaxation. Higher doses may result in memory loss (amnesia) and abnormal mental processes, such as dissociation, while long-term use has been associated with neurocognitive disorders and symptoms of psychosis, among other risks. Based on these effects, benzodiazepines have been utilized in the treatment of anxiety, seizures, insomnia, muscle cramps and spasms, and alcohol withdrawal. These drugs are also administered as premedical treatment for various medical as well as dental procedures.

The length of activity of benzodiazepines has been used as a criterion in describing subgroups of these drugs. Those with short and intermediate activity are generally used in the treatment of insomnia, whereas the longer-acting drugs are administered to patients diagnosed with anxiety.

Background

Benzodiazepines have long been considered safe and effective when administered for a short term, although reports have indicated that certain patients may experience cognitive impairment or other adverse effects, including aggressive behavior or worsening levels of agitation. Long-term treatment using benzodiazepines has also been controversial, largely due to reports on adverse psychological and physical effects, coupled with a decrease in drug effectiveness, withdrawal symptoms, and drug dependence. Based on reports of adverse effects caused by long-term administration of benzodiazepines, cessation of intake of this particular drug generally results in improvement of physical as well as mental health. Elderly patients receiving benzodiazepines have a higher risk for adverse drug effects, which has resulted in benzodiazepines' inclusion in the Beers Criteria (also called the Beers List) of potentially inappropriate drugs for older adults.

The use of benzodiazepines during pregnancy has also been under intense scrutiny. Although these specific medications are not considered major teratogens, a number of case reports have suggested an association between the use of benzodiazepines and cleft palate, a congenital deformity involving the roof of the mouth. In addition, reports on neurobehavioral effects on newborns born to women receiving benzodiazepines have been published, indicating a potential prenatal route of exposure and development of withdrawal symptoms in the newborn. Furthermore, these drugs could also be administered at significantly higher doses, often resulting in deep unconsciousness, coma, or pauses in breathing, alternating with choking during sleep (sleep apnea). However, benzodiazepine users who become pregnant are strongly advised to consult a health care provider before stopping use, as the effects of sudden withdrawal could potentially pose a greater risk to a fetus than continued use.

Despite their negative side effects, benzodiazepines are less toxic compared to barbiturates, their predecessor drugs. More importantly, the administration of benzodiazepines rarely results in death when taken alone. However, when this drug is received together with other depressants, such as opioids or ethanol, the risk for toxicity, as well as fatal overdose, significantly increases. Benzodiazepines are, therefore, among the most commonly misused medications that are often taken with other frequently abused drugs.

Impact

The introduction of benzodiazepines was initially positively accepted in clinics in the 1970s; however, by the 1980s, concerns regarding its safety arose, particularly in relation to drug dependence. Historically, benzodiazepines were implicated in the most comprehensive class-action lawsuit that was directed against drug manufacturers in the United Kingdom. The class-action lawsuit comprised fourteen thousand patients as well as close to two thousand law firms that claimed that the drug manufacturers were aware of the risk of benzodiazepine dependence yet deliberately withheld such information from physicians. Simultaneously, around 120 physicians and fifty health agencies were brought to court by patients who filed cases regarding the adverse effects of benzodiazepine dependence and withdrawal. Such cases have prompted physicians to require their patients to sign consent forms prior to treatment using benzodiazepines so that they have been warned of the possible risk of drug dependence. These court cases did not result in a verdict, mostly because of the withdrawal of legal aid to the patients, as well as allegations that certain expert witnesses and attending physicians were determined to have conflicts of interest. The cases also resulted in modifications in British law, subsequently making it more difficult to file class-action lawsuits.

Despite the growing number of reports on potential drug dependence on benzodiazepines, their use as an antidepressant continued to increase over time, mainly as a short-term treatment approach. This shorter duration of usage was mainly based on the findings of previous reports that dependence on benzodiazepines was observed in patients who received the drug for more than six months. Benzodiazepines are less frequently administered for the treatment of insomnia, having been replaced by non-benzodiazepines such as zolpidem (trade name Ambien) and zaleplon (trade name Sonata, among others). The molecular structure of these non-benzodiazepines is highly similar to that of benzodiazepines; therefore, these target the same protein receptor on the cell membrane of nerve cells, resulting in sedation.

Other side effects of benzodiazepines include driving impairment, toxicity, and death due to drug overdose or drug withdrawal. Older adult patients who received benzodiazepines for more than six months have also been observed to undergo a decline in cognition and memory and suffer frequent falls.

In early 2014, the benzodiazepine drug alprazolam (trade name Xanax) was reclassified as a Schedule 8 drug or a controlled substance, indicating that this medication has a high risk for abuse as well as addiction. This drug is, therefore, dispensed only with a physician’s authority. Furthermore, Schedule 8 drugs are often prescribed by specialists, which include psychiatrists and pediatricians. Research investigations have determined that an individual who receives a benzodiazepine for more than four weeks is highly likely to develop withdrawal symptoms when suddenly removed from a treatment regimen. Therefore, physicians often prescribe this drug for one to two weeks in order to decrease the risk of drug dependence.

Bibliography

"American Geriatrics Society 2015 Updated Beers Criteria for Potentially Inappropriate Medication Use in Older Adults." Journal of the American Geriatrics Society, vol. 63, no. 11, 2015, doi:10.1111/jgs.13702. Accessed 11 Feb. 2025.

Baumeister, David, et al. "Legal Highs: Staying on Top of the Flood of Novel Psychoactive Substances." Therapeutic Advances in Psychopharmacology, vol. 5, no. 2, 2015, pp. 97–132, doi:10.1177/2045125314559539. Accessed 11 Feb. 2025.

Bounds, Connor, and Preeti Patel. "Benzodiazepines." StatPearls, StatPearls Publishing, 30 Jan. 2024. NIH National Library of Medicine - National Center for Biotechnology Information, www.ncbi.nlm.nih.gov/books/NBK470159/. Accessed 11 Feb. 2025.

Brett, Jonathan, and Bridin Murnion. "Management of Benzodiazepine Misuse and Dependence." Australian Prescriber, vol. 38, no. 5, 2015, pp. 152–55.

Ciraulo, Domenic A., and Clifford M. Knapp. "Sedative-Hypnotics." Lowinson and Ruiz's Substance Abuse: A Comprehensive Textbook, edited by Pedro Ruiz and Eric C. Strain, 5th ed., Lippincott Williams & Wilkins, 2011, pp. 255–66.

Dell'Osso, Bernardo, et al. "Bridging the Gap between Education and Appropriate Use of Benzodiazepines in Psychiatric Clinical Practice." Neuropsychiatric Disease and Treatment, vol. 11, 2015, pp. 1885–909, doi:10.2147/NDT.S83130. Accessed 11 Feb. 2025.

Islam, M. Mofizul, et al. "Prescribing and Dispensing of Benzodiazepines: Implications for Dependence and Misuse." Neuropathology of Drug Addictions and Substance Misuse, edited by Victor R. Preedy, vol. 3, Academic Press, 2016, pp. 283–92.

Konopka, Anna, et al. "Benzodiazepine Misuse and Addiction: Risk Factors and Adverse Behavioral Aspects." Neuropathology of Drug Addictions and Substance Misuse, edited by Victor R. Preedy, vol. 3, Academic Press, 2016, pp. 327–33.

Liebrenz, Michael, et al. "High-Dose Benzodiazepine Dependence: A Qualitative Study of Patients' Perception on Cessation and Withdrawal." BMC Psychiatry, vol. 15, no. 116, 2015, doi:10.1186/s12888-015-0493-y. Accessed 11 Feb. 2025.

Liebrenz, Michael, et al. "High-Dose Benzodiazepine Dependence: A Qualitative Study Of Patients’ Perceptions on Initiation, Reasons for Use, and Obtainment." PLoS ONE, vol. 10, no. 11, 2015.

Palmaro, Aurore, et al. "Benzodiazepines and Risk of Death: Results from Two Large Cohort Studies in France and UK." European Neuropsychopharmacology, vol. 25, no. 10, 2015, pp. 1566–77.

Sachdeva, Ankur, et al. "Alcohol Withdrawal Syndrome: Benzodiazepines and Beyond." Journal of Clinical and Diagnostic Research, vol. 9, no. 9, 2015.

Zhong, GuoChao, et al. "Association between Benzodiazepine Use and Dementia: A Meta-Analysis." PLoS ONE, vol. 10, no. 5, 2015.