Francis is an 84-year-old female who fell going to the bathroom one night and sustained a right hip fracture. She had a period of confusion in the hospital that has now resolved. She has returned home after a prolonged hospitalization on her usual medications of ramipril, hydrochlorothiazide, ASA, alendronate, Vitamin D, calcium, and l-thyroxine. In addition, she is also now taking quetiapine, and omeprazole. Her husband finds her to be frailer than before her admission and asks if any of her medications could be contributing to a risk for further falls.
Issue
What does the evidence say about the association between medications and fall risk?
Bottom Line
The majority of falls are multifactorial and related to the interplay between factors that may include age; female gender; mobility impairments; activity level; visual impairments; cognitive impairments; postural instability; chronic diseases and medications.[i] Medication modification is one of the more important interventions available to reduce the risk for falls, including considering both types of drugs and their doses given the dose-dependent nature of the risk demonstrated in many studies.
For Francis, consideration could be given to discontinuing hydrochlorothiazide and quetiapine, given the more specific association with falls.
Evidence
Intuitively, one would expect that drugs that can increase the risk for falls would be those that lead to:
- Hypotension/Postural Hypotension.
- Extrapyramidal effects.
- Ataxia/gait disturbances.
- Visual changes.
What is the evidence we actually have relating medications and falls? The strongest evidence of an association between medications and falls is for the psychotropics. Weaker evidence is available for some cardiovascular drugs, opioids, hypoglycemics, anti-epileptics and anti-parkinson’s medications.
Psychotropics
Psychotropics include antidepressants, sedative hypnotics, and neuroleptics. Using a case-control design, Ray et al[ii] reported on the risk of falls and fractures related to the use of these drugs and demonstrated an odds ratio of 1.9 (95% CI 1.3 - 2.8) for tricyclic antidepressants; 2.0 (95% CI 1.6 - 2.6) for antipsychotics; and 1.8 (95% CI 1.3 - 2.4) for long-acting hypnotics-anxiolytics. For all three of these drug classes, the risk was shown to rise with increasing dose.
In contrast, they did not demonstrate an increased odds ratio for short-acting hypnotics-anxiolytics (OR 1.1, 95% CI 0.8 - 1.6). Hartikainen et al[iii] completed a systematic review to further explore the issue of hypnotic-anxiolytics half-life and falls risk. In their review, benzodiazepines were associated with falls or fall-related fractures in 17 studies. The risk of falls was increased after a new prescription; with long-term use; and regardless of half-life. Concomitant use of two or more benzodiazepines increased fracture risk two-fold. Only three studies did not demonstrate an association between benzodiazepine use and fall risk. One non-benzodiazepine study was also found using zolpidem and demonstrated a similar risk to the benzodiazepines. Landi et al[iv] using an observational design also demonstrated a similar fall risk with long-acting benzodiazepines (adjusted OR 1.45; 95% CI 1.00 – 2.19) and short-acting benzodiazepines (adjusted OR 1.32; 95% CI 1.02 – 1.72).
Thapa et al[v] studied the effect of antidepressants and risk for falls in a nursing home population using a retrospective design. They demonstrated that amongst new users of antidepressants, adjusted rate ratios for falls were 2.0 (95% CI 1.8 - 2.2) for tricyclic antidepressants; 1.8 (95% CI 1.6 - 2.0) for SSRI’s; and 1.2 (95% CI 1.0 - 1.4) for trazodone. Similarly to Ray et al, they also demonstrated a dose-dependent increase in fall risk with higher doses of the drugs reaching 2.4 (95% CI 2.1 - 2.8) for the equivalent of 50 mg of amitriptyline; and 1.9 (95% CI 1.7 – 2.2) for the equivalent of 20 mg of fluoxetine. Elevated fall rates were shown to persist for at least 180 days after initiation of the drug. In their systematic review, Hartikainen et al also looked at antidepressants and found an association between falls and tricyclic or SSRI use in 12 studies with no association found in five studies. Risks varied from 1.20 to 6 fold, remained elevated in long-term use, and were dose-dependent.
Less data is available for the antipsychotics. However, what is available also suggests an increased risk . Hartikainen et al demonstrated that antipsychotics were associated with an increased risk for falls in a limited number of studies. However, in one Swedish study only two included atypical antipsychotics and neither risperidone (OR 1.26; 95% CI 0.81 – 1.95) nor olanzapine (OR 1.89; 95% CI 0.99 – 3.62) was significantly associated with falls risk. There was a dose-dependent risk demonstrated for risperidone with a higher risk above two mg/d. Three studies did not demonstrate an increased risk. More recently, Sterke C et al[vi] using a prospective design with nursing home residents demonstrated a hazard ratio (HR) of 2.78 (95% CI 1.49-5.17) with antipsychotic use, and that fall risk was increased even on low doses of an antipsychotic. A dose-response was seen, similar to that noted by Hartikainen.
Other Drugs
In an early meta-analysis, Leipzig et al[vii] examined a number of cardiovascular drugs and, while demonstrating a trend towards an increased risk for falls, only diuretics showed a statistically significantly increased risk (OR 1.08; 95% CI 1.02 – 1.16). Cardiovascular drugs were also reviewed in the Hartikainen et al systematic review. Three papers reported an association between cardiovascular drugs and falls risk, including antihypertensives (OR 2.4 for injurious falls; 95% CI 1.1 – 6.5); beta-blockers (OR 2.2; 95% CI 1.2 – 4.0) and peripheral vasodilators (OR 3.8; 95% CI 1.4 – 10.2) for recurrent falls; and nitrates (OR 2.2; 95% CI 1.3 – 3.9) for any falls. No association was demonstrated in 9 studies. Considerable heterogeneity was also noted.
For opioids, Vestergaard et al[viii] used a case control design and demonstrated an increased fracture risk with the use of morphine (OR 1.47; 95% CI 1.37 - 1.58); fentanyl (OR 2.23; 95% CI 1.89 - 2.64); oxycodone (OR 1.36; 95% CI 1.08 - 1.69); tramadol (OR 1.54, 95% CI 1.49 - 1.58); and codeine (OR 1.16, 95% CI 1.12 - 1.20). Other studies have shown a consistent pattern, and that higher total daily doses of opioids were associated with recurrent falls.
Other medications that have been examined include hypoglycemics, where the risk appears to be related to the risk for producing hypoglycaemia rather than to the drugs themselves, and is greatest with insulin. Anti-epileptics have shown an association in some studies, though primarily with older agents such as phenytoin, phenobarbital, or carbamazepine; there is limited or no information related to risks with newer agents. Anti-Parkinson’s agents have been studied in a large case-control trial[ix] and an association reported for an increased risk of fracture with high doses of levodopa, dopamine-receptor agonists, and MAO-B inhibitors.
Polypharmacy
Polypharmacy is often cited as a risk factor for falls. Ziere et al[x] looked at the association between polypharmacy, defined as use of 3 or more medications, and falls using a population-based cross-sectional study. They demonstrated that the risk for falls increased significantly with the numbers of drugs used on a daily basis, even after adjusting for many other potential confounders. However, the association was shown only when the medication regimen included at least one drug associated with an increased risk for falling. Therefore, polypharmacy per se does not appear to be a risk factor for falls other than that as the numbers of drugs increase, the risk for including a drug that increases falls risk increases.
References
[i] De Jong M, Van der Elst M, Hartholt K. Drug-related falls in older patients: implicated drugs, consequences, and possible prevention strategies. Ther Adv Drug Saf 2013;4(4):147-54.
[ii] Ray W, Griffin M et al. Psychotropic Drug Use and the Risk of Hip Fracture. NEJM 1987; 316:363-9.
[iii] Hartikainen S, Lonnroos E, Louhivuori K. Medication as a Risk Factor for Falls: Critical Systematic Review. J Geront Medical Sciences 2007;62A:1172-81.
[iv] Landi F et al. Psychotropic Medications and Risk for Falls Among Community-Dwelling Frail Older People: An Observational Study. J Geront Medical Sciences 2005;60A:622-6.
[v] Thapa PB et al. Antidepressants and the Risk of Falls Among Nursing Home Residents. NEJM 1998;339(13):875-82.
[vi] SterkeC et al. New Insights: dose-response relationship between psychotropic drugs and falls: a study in nursing home residents with dementia. J Clin Pharmacol 2012;52:947-55.
[vii] Leipzig RM et al. Drugs and Falls in Older People: a systematic review and meta-analysis. JAGS 1999; 47:40-50.
[viii] Vestergaard P, Rejnmark L, Mosekilde L. Fracture Risk Associated with the Use of Morphine and Opioids. J Intern Med 2006; 260(1):76-87.
[ix] Vestergaard P, Rejnmark L, Mosekilde L. Fracture Risk Associated with parkinsonism and anti-Parkinson drugs. J Calcified Tissue Int 2007; 81(3):153-61.
[x] Ziere G et al. Polypharmacy and falls in the middle age and elderly population. Br J Clin Pharmacol 2006; 61(2):218-23.