Fall Risk and Benzos – Is Trazodone Really the Knight in Shining Armor?

Author(s)
Anthony M. Todd, PharmD
Nicole A. Slater, PharmD, BCACP

Reviewed By
Michelle Balli, PharmD, BCACP
Amie Blaszczyk, PharmD, BCPS, BCGP
Emily Leppien, PharmD, BCPS

Citation
Bronskill SE, Campitelli MA, Iaboni A, Herrmann N, Guan J, Maclagan LC, Watt J, Rochon PA, Morris AM, Jeffs L, Bell CM, Maxwell CJ. Low-Dose Trazodone, Benzodiazepines, and Fall-Related Injuries in Nursing Homes: A Matched-Cohort Study. J Am Geriatr Soc. 2018; 66(10): 1963-1971. doi: 10.1111/jgs.15519.

The Problem

Older adults are often tormented by insomnia, pain, and other comorbidities that impact their quality of life and overall health.  Medication therapy is often sought to treat and manage these diseases, but healthcare providers often overlook the risks of prescribing medications to patients who are older, frail, and at high risk for falls.

 

Trazodone is increasingly prescribed instead of benzodiazepines for elderly nursing home residents.¹ Neither the Beers Criteria nor the STOPP/START Criteria mention trazodone as a potentially inappropriate medication for use in the older adults — perhaps due to a lack of studies demonstrating harm.^2,3,4  Is trazodone really safer for patients than benzodiazepines?

 

What’s Known

It is widely known that the use of psychotropic drugs, such as antidepressants and antipsychotics, are associated with an increased risk of falls, particularly in nursing home residents.^5,6,7 The American Geriatric Society recommends that benzodiazepines be avoided in the older adults since this population is more susceptible to cognitive impairment, delirium, falls, fractures, and motor vehicle crashes. Benzodiazepine use may be considered if there is a compelling indication for their use, such as a seizure disorder or severe generalized anxiety disorder.² The STOPP/START criteria recommends that benzodiazepines be discontinued in older adults who’ve experienced a fall within the past three months, have acute or chronic respiratory failure, or if used for longer than four weeks, regardless of indication.³

 

What’s New

A recent study compared the risk of falls associated with trazodone and benzodiazepine use.⁴  This was a retrospective cohort study evaluating fall risk in nursing home residents in Ontario, Canada. The Continuing Resident Reporting System database identified 595,898 full medical assessments of 169,595 residents aged ≥ 66 years between April 1, 2010, and March 31, 2015. Assessments were performed using the Resident Assessment Instrument Minimum Data Set (RAI-MDS) version 2.0, a validated tool. An assessment was excluded if no drugs were prescribed in the year before the assessment, if the resident was comatose or completely bedbound at the time of the assessment, or if the resident had received palliative care in the 180 days before the assessment.

 

Information on dispensed drug therapies were obtained from the Ontario Drug Benefit database.  The investigators identified nursing home residents who were newly initiated on low-dose trazodone (≤150 mg) or a benzodiazepine, defined as a lorazepam 2.5 mg per day dose or equivalent.⁴

 

The primary outcome was the first occurrence of a composite of fall-related emergency department (ED) visit or an acute care hospitalization within 90 days of exposure to either low-dose trazodone or benzodiazepines. Secondary outcomes included a composite of fall-related ED visits or acute care hospitalizations with a hip or wrist fracture diagnosis within 90 days of exposure. Residents were followed in an intent-to-treat fashion such that switching drug exposure groups and/or discontinuation were permitted, but the individuals remained in their initial groups. Propensity score matching was used to compare residents with similar baseline characteristics, including comorbidities, cognitive status, and fall risk.⁴

 

Of the 169,595 patients assessed, new users of low-dose trazodone (n=9,650) and benzodiazepines (n=10,642) within 7 days before or after clinical assessment were identified. Propensity score matching produced 7,792 analytical pairs. The median dose of trazodone used was 50 mg/day (interquartile range 25-51.7 mg/day), whereas the median dose of benzodiazepines used was 1.07 mg/day lorazepam equivalents (interquartile range 0.75-2.14 mg/day). See Table 1 for Results.

 

Table 1. Cumulative Incidence of Falls

Outcome	Trazodone Users, %	BZD Users, %	Difference in Outcomes, % (95% CI)	Hazard Ratio (95% CI)
Primary Outcome
Fall-related ED visit or acute care hospitalization within 90 days	5.74	6.03	-0.29 (-1.02 to 0.44)	0.95 (0.83 to 1.08)
Secondary Outcomes
Fall-related (with hip or wrist fracture diagnosis) ED visit or acute care hospitalization within 90 days	1.22	1.54	-0.32 (-0.68 to 0.04)	0.79 (0.60 to 1.04)
Censoring on exposure drug discontinuation or switching	5.97	5.92	0.05 (-1.01 to 1.11)	0.96 (0.82 to 1.14)
New low-dose trazodone vs new low-dose benzodiazepine subgroup	5.71	5.79	-0.08 (-1.00 to 0.83)	0.99 (0.84 to 1.16)

^{BZD = Benzodiazepine
Data extracted from Bronskill et al. J Am Geriatr Soc. 2018;66(10):1963-1971. Table 2. Association Between Initial Drug Exposure and Fall-Related Injuries for Ontario Nursing Home Residents Dispensed Low-Dose Trazodone or a Benzodiazepine, Overall and According to Subgroup: April 1, 2010, to March 31, 2015}

 

There were no statistically significant differences found among the outcomes. Low-dose trazodone use was no safer than benzodiazepine use with respect to fall-related injuries, ED visits, or acute care hospitalizations within 90 days of exposure. Although the data was not reported in the study, a random sample of residents with no history of exposure to either drug had a lower risk of fall-related outcomes (4.1%) than either study cohort. The authors concluded that more vigilance related to off-label prescribing of trazodone is needed.

 

Our Critical Appraisal

This trial had several strengths. First, the RAI-MDS version 2.0, which contains several validated scales measuring health status and function, was used to determine a validated frailty index for each nursing home resident.  This allows the investigators to accurately determine and compare  frailty status in the two cohorts. Second, the authors accounted for several potential confounding variables and the results are more likely to represent the effects caused by exposure to the index drugs. Third, the patients were followed in an intent-to-treat fashion.

 

However, the study also has some limitations. Its retrospective design leads to the possibility of missing information and there are likely potential confounders that are not accounted for in the analysis. Second, the trial looked only at incidence of falls resulting in ED visits or hospitalizations, which likely underestimates the true incidence of fall-related injuries as some falls undoubtedly did not results in an ED visit or hospitalization. Third, the authors did not have information regarding the indications for the drug exposures. Although the median and range of doses of trazodone and benzodiazepines used fell within the recommended doses used for insomnia, it is unclear if they were specifically used for sleep.^8,9 Indeed, the authors acknowledge that the patients could have received benzodiazepines divided throughout the day for an indication other than insomnia. Fourth, the authors do not report all medications residents were taking, so the falls could have been attributable to other medications — for example, antihypertensives causing orthostasis or insulin causing hypoglycemia. Finally, this study was conducted in a nursing home population, so the results might not apply to community dwelling patients.

 

The Bottom Line

So, is trazodone really the knight in shining armor? We think not. Based on the results of this study, trazodone is no safer than benzodiazepines in elderly nursing home residents.  Thus there is no real benefit to prescribing trazodone over benzodiazepines for sleep. This could partly be explained by the mechanism of action of trazodone. In addition to its serotonergic effects, trazodone significantly blocks histamine (H1) and alpha1-adrenergic receptors, and these CNS effects likely increase a patient’s risk of falls.⁸ More studies are needed to determine the impact of trazodone on fall risk. Until more evidence is available, we believe both trazodone and benzodiazepines should be avoided in older adults. For now, nonpharmacological modalities such as cognitive behavioral therapy and sleep hygiene recommendations should be employed.^6,7,10

 

The Key Points

• Trazodone is increasingly being prescribed for insomnia in the elderly perhaps under the assumption that it is safer than benzodiazepines.
• The AGS Beers Criteria make no recommendation regarding the use of trazodone, not because evidence demonstrate its safety, but due to a lack of evidence demonstrating harm.
• A recently published retrospective cohort study⁴ demonstrated that low-dose trazodone was no safer than benzodiazepine use with regard to fall-related injuries, ED visits, or hospitalizations.
• Nonpharmacological modalities, such as cognitive behavioral therapy and sleep hygiene should be employed in the older adults to minimize the risk of falls.