The first benzodiazepine (BZD) compound (chlordiazepoxide) was discovered in the 1950s, and since its approval for use, other compounds including diazepam, flurazepam, flunitrazepam, and clonazepam have been developed.1 BZDs gained prominence in the 1970s by offering a safer alternative to barbiturates and barbiturate-like substances (eg, chloral hydrate).2
Of the BZDs available, estazolam, temazepam, flurazepam, quazepam, and triazolam are approved for use in insomnia by the US Food and Drug Administration (FDA).3 Triazolam is FDA-indicated for sleep onset insomnia, and the others are indicated for both sleep onset and sleep maintenance insomnia.3 Drug classes such as benzodiazepine receptor agonists (BZRAs [eg, zolpidem, zaleplon, eszolpiclone]), melatonin agonists, and selective serotonin reuptake inhibitors (SSRIs) have replaced BZDs to some extent over the years; however BZDs are still widely prescribed and frequently used, particularly in institutionalized older populations.4,5 Although this article focuses on the nuances of BZD therapy for insomnia, nonpharmacologic approaches (such as sleep restriction, cognitive-behavioral therapy, and sleep hygiene) should also be used.
BZDs exert their sedating effect by binding specific benzodiazepine-type receptors on the gamma-aminobutyric acid (GABA) A receptor complex. This leads to an enhancement of GABA, which is the primary inhibitory neurotransmitter in the central nervous system (CNS).1,4 BZD activity in the spinal cord, brain stem and cerebellum, and the limbic and cortical areas results in muscle relaxation, ataxia, and behavioral changes.1
Pharmacokinetic and Pharmacodynamic Changes in Older Adults
Although BZDs have similar mechanisms of action, they differ in lipophilicity and pharmacokinetic profile, which has implications on drug selection (Table 1).3,4 Physiologic changes that occur with aging affect drug pharmacokinetics and pharmacodynamics. A detailed discussion of many of these changes is beyond the scope of this article; however, some are particularly relevant to BZDs.
Dose and Duration of Benzodiazepines in Older People
Although not evident on routine clinical tests, there is an age-related decrease in liver size (25%–35%) and liver blood flow (40%), and a decrease in the rate of protein synthesis.6 Drugs that are dependent on blood flow are cleared less efficiently as hemoperfusion decreases. Drugs that are metabolized by microsomal cytochrome P450 enzymes (CYP) in the liver may also undergo changes in rate of drug clearance, which can be further complicated by drugs that interact with one another.6,7 Because older adults often have extensive and complex medication regimens, the clinician must be mindful of how drug interactions further affect BZD metabolism and clearance. With the exception of lorazepam, oxazepam, and temazepam, BZDs are metabolized by CYP3A4. Inhibitors of CYP3A4 (eg, clarithromycin and ketoconazole) can increase the risk of BZD toxicity, whereas inducers of CYP3A4 (eg, rifampin and carbamazepine) can decrease BZD effectiveness8 (Table 2).
CYP3A4-Mediated Drug Interactions
Alterations in drug distribution and decreased drug elimination that occur with age can increase drug half-life, making accumulation more likely.6 Both brain size and the number of GABA-A BZD receptors decrease with age. The remaining receptors are more sensitive to BZD therapy, making older people more likely to experience pronounced sedation or cognitive dysfunction.9–11 Older adults also show a decrease in homeostatic mechanisms, which can contribute to postural hypotension, syncope, and falls.6 Warning labels on BZDs are strongly against use with concomitant CNS depressants, especially opioids, due to the risk of profound sedation, respiratory depression, coma, and death.12 FDA warnings about co-prescribing of BZDs and opioid analgesics have drastically increased since 2002. Given the opioid abuse epidemic in America, prescribers should avoid concurrent BZDs and opioids whenever possible.
Meta-analyses of studies comparing BZDs and placebo have found BZDs showed significant improvement in subjective reports of sleep quality and decrease in nighttime awakenings.9 These studies indicate that there were insufficient data to analyze sleep onset latency. BZDs compared to BZRAs showed no significant difference in sleep quality and no significant difference in adverse effects.9 Various trials of temazepam in older adults have shown improvements in sleep onset latency and waking after sleep onset, but no improvement in total sleep time.3 Evidence for these trials was insufficient or low strength. Overall evidence to support long-term use of BZDs is lacking.4
Benzodiazepine-Associated Adverse Effects
Older adults are disproportionately affected by adverse drug effects and nearly 7 times more likely to be subsequently hospitalized than younger people.13 Adverse effects with BZDs can been seen at therapeutic doses but are often dose-related. Confusion, impaired psychomotor performance (including slower reaction time), and decreased ability to perform simple tasks have been noted.1,5 Because drug levels can remain sufficiently high due to reduced clearance in older adults, next-day sedation is more common with long-acting agents.14
Loss of memory has been reported with BZDs, most frequently triazolam and lorazepam.4,9 New information acquired post-drug administration (anterograde memory) is consistently impaired by BZDs, whereas information synthesized pre-drug administration (retrograde memory) is unaffected.1 Combining alcohol with BZDs makes the effects on memory even more pronounced.15 BZD-associated cognitive impairment may manifest as increased forgetfulness, difficulty with short-term recall, and anterograde amnesia. The insidious onset of these symptoms can be mistaken for dementia, also termed pseudo-dementia.5,15 Cognitive function usually improves once the BZD is tapered or discontinued.5,14
Complex sleep-related behaviors performed while not fully awake such as driving, eating, and having sex have been reported with BZDs.16 Residual CNS effects that impair next-day performance and increase the risk of motor vehicle crashes are possible.17 Interestingly, BZDs can produce paradoxical effects, some of which may result in legal consequences. Acute excitement, anxiety, hyperactivity, disinhibition, hostility, aggressive impulses, assault, and rage have all been recorded.15 These effects are complex and mediated by other factors such as BZD dose, concurrent alcohol use, and patient personality factors.18
Falls are an ever-increasing yet likely underrecognized health concern in the aging population. BZDs increase the risk of falling by 50%, with a 1-year mortality rate thereafter of 20%.19 Associated hip fracture is often life-altering, leading to a loss of physical functioning, confidence, and independence. The incidence of BZD-associated falls and hip fractures is higher during the first 2 weeks of drug initiation, and increases with dose and when antihypertensives, antidepressants, and antipsychotics are co-prescribed.14,18,19
Positions on the Matter
The American Geriatrics Society publishes the Beers Criteria based on a systematic, comprehensive literature review by an interdisciplinary panel of experts in geriatric care and pharmacotherapy.17 It outlines potentially inappropriate medications for use in people age 65 years and older and serves as a reference for safe prescribing in older people.17 The Beers Criteria broadly recommend that BZDs be avoided in older adults due to increased sensitivity, decreased metabolism caused by long-acting ones, and increased risk of adverse effects including falls, cognitive impairment, and delirium.17 Long-acting agents are noted as exceptions, as they “may be appropriate for seizure disorders, rapid eye movement sleep behavior disorders, benzodiazepine withdrawal, ethanol withdrawal, severe generalized anxiety disorder, and periprocedural anesthesia.”17 The criteria strongly recommend to “avoid” concurrent use of three or more CNS-active drugs and “minimize the number of CNS-active drugs” overall due to the risk of falls and fractures because of the potential drug interaction between BZDs and other CNS-active drugs.17
Guidelines set forth by the American Academy of Sleep Medicine20 are not limited in scope to the treatment of older adults and offer a different perspective on BZD use. Based on an exhaustive review of the literature, triazolam and temazepam are recommended for sleep onset insomnia. Temazepam is additionally recommended for sleep maintenance insomnia. Recommendations were not possible for estazolam or flurazepam due to inadequate data for analysis.21
Before considering a pharmacologic agent to treat insomnia, a clinician should first encourage good sleep hygiene and consider nonpharmacologic therapies. Next, a thorough review of current medications should be done to screen for potential drug-drug interactions and agents that may be contributing to insomnia. It is important to specifically ask about over-the-counter and herbal products because some patients do not consider them “medicines.” Low doses of mildly sedating antidepressants are preferred over BZDs and may offer added benefit in patients with comorbidities such as depression or history of substance abuse.
If a BZD is deemed necessary, patient report of daytime functioning, difficulty with sleep onset, or difficulty with sleep maintenance can help guide treatment choice. Short-acting BZDs are preferred for complaints of falling asleep whereas intermediate-acting would be beneficial for maintaining sleep.4 Long-acting agents should be avoided in older adults for treating insomnia unless comorbidities (eg, seizure disorder, restless leg syndrome, or alcohol withdrawal) strongly justify their use.17
Given alterations in drug concentration and response in older adults, the aphorism “start low, go slow” captures a reasonable dosing approach. The initial starting dose of BZDs should be 50% lower than would be used in younger people (Table 1). Titration should be based on clinical response in small dosing increments.6 Older people should be maintained on the minimum effective dose to achieve treatment goals.
Because insomnia is often not a nightly experience, routine BZD administration may not be warranted. Intermittent dosing (eg, 3–4 nights per week) is an alternative that has been used to minimize the risk of tolerance or abuse.22 A strategy that is not recommended is to administer the BZD whenever the patient awakens from nightly sleep.21 High morning drug levels can interfere with cognitive and physical functioning throughout the day.
BZDs are FDA-indicated for short-term use in insomnia, in part because of risks of serious adverse effects including associated falls, fractures, and cognitive and behavioral changes.3 Long-term BZD use (more than 4 weeks) in older adults should be avoided;22 however many patients have been on BZDs for months to many years, making discontinuing them a complex and lengthy task. Abrupt discontinuations or robust reductions of high-dose or long-term BZDs can result in withdrawal symptoms such as agitation, seizures, insomnia, muscle spasms, nightmares, and psychosis.15 Specific tapering protocols vary; however, slower tapers (over the course of weeks to months) are more successful and better tolerated. One approach is to reduce the BZD dose by 25% every 1 to 2 weeks,14 but this may still be too aggressive for some patients to tolerate. The overall taper duration should be guided by patient willingness to properly adhere to the regimen and the presence or absence of withdrawal symptoms.
- Lader M. Benzodiazepines revisited--will we ever learn?Addiction. 2011;106:2086–2109. doi:. doi:10.1111/j.1360-0443.2011.03563.x [CrossRef]
- Asnis GM, Thomas M, Henderson MA. Pharmacotherapy treatment options for insomnia: a primer for clinicians. Int J Mol Sci. 2016;17:50. doi:. doi:10.3390/ijms17010050 [CrossRef]
- Wilt TJ, MacDonald R, Brasure M, et al. Pharmacologic treatment of insomnia disorder: an evidence report for a clinical practice guideline by the American College of Physicians. Ann Intern Med. 2016;165:103–112. doi:. doi:10.7326/M15-1781 [CrossRef]
- Morin AK, Jarvis CI, Lynch AM. Therapeutic options for sleep-maintenance and sleep-onset insomnia. Pharmacotherapy. 2007;27(1):89–110. doi:. doi:10.1592/phco.27.1.89 [CrossRef]
- Bogunovic OJ, Greenfield SF. Practical geriatrics: benzodiazepines among elderly patients. Psychiatr Serv.2004;55(3):233–235. doi:. doi:10.1176/appi.ps.55.3.233 [CrossRef]
- Turnheim K. When drug therapy gets old: pharmacokinetics and pharmacodynamics in the elderly. Exp Gerontol. 2003;38:843–853. doi:. doi:10.1016/S0531-5565(03)00133-5 [CrossRef]
- Hämmerlein A, Derendorf H, Lowenthal DT. Pharmacokinetic and pharmacodynamic changes in the elderly--clinical implications. Clin Pharmacokinet. 1998;35(1):49–64. doi:10.2165/00003088-199835010-00004 [CrossRef]
- Therapeutic Research Center. Cytochrome P450 drug interactions. Pharmacist's Letter. May2016. https://pharmacist.therapeuticresearch.com/Content/Segments/PRL/2016/May/Cytochrome-P450-Drug-Interactions-9674. Accessed May 18, 2018.
- Glass J, Lanctot KL, Herrmann N, Sproule BA, Busto UE. Sedative hypnotics in older people with insomnia: meta-analysis of risks and benefits. BMJ. 2005;331:1169. doi:. doi:10.1136/bmj.38623.768588.47 [CrossRef]
- Cefalu CA. Theories and mechanisms of aging. Clin Geriatr Med. 2011;27:491–506. doi:. doi:10.1016/j.cger.2011.07.001 [CrossRef]
- Duncan GW. The aging brain and neurodegenerative diseases. Clin Geriatr Med. 2011;27:629–644. doi:. doi:10.1016/j.cger.2011.07.008 [CrossRef]
- US Food and Drug Administration. New safety measures announced for opioid analgesics, prescription opioid cough products, and benzodiazepines. https://www.fda.gov/drugs/drugsafety/informationbydrugclass/ucm518110.htm. Accessed May 12, 2018.
- Budnitz DS, Pollock DA, Weidenbach KN, Mendelsohn AB, Schroeder TJ, Annest JL. National surveillance of emergency department visits for outpatient adverse drug events. JAMA. 2006;296(15):1858–1866. doi:. doi:10.1001/jama.296.15.1858 [CrossRef]
- Markota M, Rummans TA, Bostwick JM, Lapid MI. Benzodiazepine use in older adults: dangers, management, and alternative therapies. Mayo Clin Proc. 2016;91(11):1632–1639. doi: . doi:10.1016/j.mayocp.2016.07.024 [CrossRef]
- Lader M. Benzodiazepine harm: how can it be reduced?Br J Clin Pharmacol. 2012;77(2):295–301. doi . doi:10.1111/j.1365-2125.2012.04418.x [CrossRef]
- Triazolam prescribing information. https://www.drugs.com/pro/triazolam.html. Accessed May 12, 2018.
- American Geriatrics Society 2015 Beers Criteria Update Expert Panel. American Geriatrics Society 2015 updated Beers criteria for potentially inappropriate medication use in older adults. J Am Geriatr Soc. 2015;63(11):2227–2246. doi:. doi:10.1111/jgs.13702 [CrossRef]
- Jones K, Nielsen S, Bruno R, Frei M, Lubman DI. Benzodiazepines--their role in aggression and why GPs should prescribe with caution. Aust Fam Physician. 2011;40(11):862–865.
- Cumming RG, Le Couteur DG. Benzodiazepines and risk of hip fractures in older people: a review of the evidence. CNS Drugs. 2003;17(11):825–837. doi:10.2165/00023210-200317110-00004 [CrossRef]
- Gurwitz JH, Rochon PUS Food and Drug Administration. Improving the quality of medication use in elderly patients: a not-so-simple prescription. Arch Intern Med.2002;162(15):1670–1672. doi:10.1001/archinte.162.15.1670 [CrossRef]
- Sateia MJ, Buysse DJ, Krystal AD, Neubauer DN, Heald JN. Clinical practice guideline for the pharmacologic treatment of chronic insomnia in adults: an American Academy of Sleep Medicine clinical practice guideline. J Clin Sleep Med. 2017;13(2):307–349. doi:. doi:10.5664/jcsm.6470 [CrossRef]
- Schuette-Rodin S, Broch L, Buysse D, Dorsey C, Sateia M. Clinical guidelines for the evaluation and management of chronic insomnia in adults. J Clin Sleep Med. 2008;4(5):487–504.
Dose and Duration of Benzodiazepines in Older People
||Starting Dose (mg)
CYP3A4-Mediated Drug Interactions