Cognitive and balance dysfunctions due to the use of zolpidem in the elderly: a systematic review

ABSTRACT. Zolpidem is one of the most widely prescribed hypnotic (non-benzodiazepine) agents for sleep disorder. Recently, an increase in the demand for this drug has been observed, mainly in the elderly population. Objective: This study aims to analyze the acute effect of zolpidem on cognitive and balance dysfunctions in the elderly population. Methods: A study was conducted by two independent researchers in four virtual scientific information bases and included randomized controlled trials. The studies evaluated elderly patients using zolpidem. Cognitive and balance dysfunctions were analyzed. Results: Six articles were included. The mean age of the participants in the studies was 69 years. The following zolpidem dosages were evaluated: 5, 6.25, 10, and 12.5 mg. Comparing zolpidem and placebo, relating to the cognitive dysfunctions, there is no statistically significant difference between the groups. However, in relation to balance dysfunctions, there is a statistically significant difference between the intervention and the comparison, favoring placebo. Conclusions: Zolpidem, even in usual doses (5 mg and 10 mg), has shown to increase the risk for balance dysfunctions. However, this does not occur in relation to cognitive changes.


INTRODUCTION
Z olpidem is one of the most internationally prescribed hypnotic (non-benzodiazepine) agents, a derivative of imidazopyridine, and has a small action as an agonist at GABA-A receptors for treatment. 1 It is used for sedation, anxiety reduction, and central muscle relaxation, and it has an anticonvulsant effect. 2 In the elderly population, as they age, the consumption of hypnotics increases. 3 Between 5 and 33% of the ageing population, from North America and the United Kingdom, received a prescription of benzodiazepine or a benzodiazepine receptor agonist for the sleep problem. 4,5 Regarding balance dysfunctions, the z-drugs (non-benzodiazepine hypnotics) are associated with elderly hospitalization for fractures, injuries, and possibly falls. [6][7][8] Besides that, cognition is critical for functional independence as people age, including whether someone can live independently, manage finances, take medications correctly, and drive safely. In addition, intact cognition is vital for humans to communicate effectively and for social life. 9 Therefore, balance and cognitive dysfunctions have an important role in the quality of life of the elderly.
Currently, there are still controversies in the scientific literature about cognitive dysfunctions and the increased risk for falls due to zolpidem use in the elderly. 8,10,11 We performed a systematic review of randomized controlled trials, aiming to analyze the acute effect of zolpidem on cognitive and balance dysfunctions in the elderly population.

METHODS
This systematic review was submitted in the International Prospective Register of Systematic Reviews (PROS-PERO) under trial registry CRD42020196434 and was conducted by the Department of Evidence-Based Medicine, Centro Universitário Lusíada, Santos, SP, Brazil.
The search for evidence was carried out independently by two researchers in the following virtual scientific information bases: Medline (PubMed), EMBASE, Central (Cochrane), Lilacs (VHL), and manual search, evaluating references from primary studies and reviews. The selection of studies was cross-checked and completed on March 4, 2021. The same search strategy was used in all scientific bases: (aged OR elderly OR older adult) AND (zolpidem OR non-benzodiazepine OR non-BZD).
The eligibility criteria were randomized clinical trials analyzing cognitive or balance dysfunctions as primary or secondary outcomes due to the acute effect of zolpidem usage in the elderly population (>60 years); no period or language limit was used; only the available full-text articles were included. The following study data were independently extracted by two researchers: name of the author and year of publication, study design, population studied, methods of intervention and comparison, the absolute number of events, means, deviation, standard error for the exams performed, and follow-up time. Data provided by the studies only in graphics were extracted using the WebPlotDigitizer software. 12 Randomized clinical trials were assessed for risk of bias according to the following criteria: focal matter, randomization, blindfold allocation, double-blind, losses less than 20%, analysis by intention to treat, prognostic characteristics, outcome (importance, time, and method), sample calculation, and JADAD (scale ranging from 0 to 5 points, which takes into account randomization, double-blinding, and losses).

RESULTS
As shown in Figure 1, 895 articles were retrieved from Medline (PubMed) database and 2,928 articles from EM-BASE, Central (Cochrane), and Lilacs databases. Excluding duplicates (2,148 studies), 1,675 articles remained to be selected; 117 articles were selected by title, 41 articles were selected by abstract, and finally, 6 articles were selected by full text. [13][14][15][16][17][18] It was not possible to perform a meta-analysis considering the variety of analyzed outcomes, lack of data, and convergent measures. Qualitative analysis of this systematic review was then performed. The baseline characteristics of the included studies are given in Table 1. The risk of biases is given in Table 2.
Considering all the studies, 145 patients were evaluated, 49 males and 68 females. The mean age of the participants in the studies was approximately 69 years. The mean washout period (crossover studies) between intervention and control (placebo) was approximately 10 days. The following zolpidem dosages were evaluated: 5, 6.25, 10, and 12.5 mg.
The results were divided into two main outcomes: (1) cognitive dysfunctions and (2) balance dysfunctions, as shown in Tables 3 and 4, respectively.    Zolpidem (5 mg)  "There was no statistically significant difference." Continue...
The obtained data showed no statistically significant difference between zolpidem (5, 6.25, 10, and 12.5 mg) and placebo in relation to short-term memory.

Long-term memory
Two studies 16,17 assessed this outcome by carrying out two tests (see Table 3): Memory recall and learning memory task (LMT).
The obtained results demonstrated no statistically significant difference between zolpidem (5, 6.25, and 12.5 mg) and placebo in relation to long-term memory.
The obtained data demonstrated no statistically significant difference between zolpidem (5, 6.25, 10, and 12.5 mg) and placebo in relation to psychomotricity.
Uemura et al. 13 performed the CFF and showed a statistically significant difference between zolpidem (5 mg) and placebo, in favor of zolpidem. Three studies 14,16,17 demonstrated no statistically significant difference between zolpidem (5, 6.25, and 12.5 mg) and placebo in relation to vision changes.

Processing, attention, and concentration
One study 16 assessed this outcome by carrying out the digit symbol substitution test (DSST) (see Table 3).
The obtained results showed no statistically significant difference between zolpidem (6.25 and 12.5 mg) and placebo in relation to processing, attention, and concentration.
Uemura et al. 13 performed two tests (body sway test and TUG) and showed no statistically significant difference between zolpidem (5 mg) and placebo in relation to balance dysfunctions. Regarding the FRT, the same study demonstrated a statistically significant difference between zolpidem (5 mg) and placebo, in favor of zolpidem.
Two studies 14,17 carried out the body sway test and showed a statistically significant difference between zolpidem (5 mg) and placebo, in favor of placebo with eyes open and closed at 1 h and 30 min, 4 h, 5 h, 6 h, and 8 h after the zolpidem, and placebo administration.
Zammit et al. 15 performed the NeuroCom EquiTest SOT and showed a statistically significant difference between zolpidem (10 mg) and placebo, in favor of placebo in conditions 1, 2, 4, 5, and 6, as well as in the balance score (CES) and in the vestibular rate.

DISCUSSION
This study is a systematic review of randomized controlled trials assessing the acute impact of zolpidem on cognitive and balance dysfunctions in the elderly population. This study showed that the use of zolpidem in the elderly is not related to cognitive dysfunctions. However, zolpidem, even in the usual dosages (5 and 10 mg) may lead to balance dysfunctions.
The use of zolpidem in the elderly with sleep disorders provides better sleep quality, adding an independent and significant contribution to the quality of life beyond psychopathological symptoms. 19 Besides that, the effects of sleep disorders are associated with a wide range of health conditions, including an increased risk of high blood pressure, diabetes, obesity, major depression, heart attack, and stroke. 20 Thus, the aim of this study is to guarantee the quality of sleep and avoid such diseases without impairing cognition, whose integrity is of utmost importance to maintain communicative skills and, therefore, social life. 9 This study showed no evidence in the scientific literature supporting any cognitive dysfunctions due to the use of zolpidem in the elderly population. However, recent randomized controlled trials evidenced a cognitive impairment relating to zolpidem in non-elderly. [21][22][23] Stranks et al. performed a systematic review and showed that the performance on attention, verbal memory, and psychomotor speed were impaired compared to the control group, based on the data of middle-aged participants (mean age was 37 years) who ingested zolpidem before bedtime. Other cognition domains, such as speed of processing and working memory, were not affected. 24 In addition to that, physicians should be aware of the greater susceptibility of the elderly to the negative consequences of zolpidem use and of other sedative hypnotics, especially the potential risk for falls, due to lower clearance rates and higher maximum serum concentration of these drugs. 25 Fractures and injuries impair the functional capacity and the health-related quality of life in the long-term follow-up. 8,26 Consequently, physicians should limit the treatment of these drugs when possible or use the lowest dose possible for patients at higher risk of imbalance. Chronic motor dysfunction of stroke patients 27 and diabetic peripheral neuropathic patients 28 present high individual risk of falling, and consequently, zolpidem should be used with caution in these patients. Also, osteoporotic patients are associated with an increased risk of related injuries, 29,30 and zolpidem use should also be taken with precaution.
High-risk group patients should receive differentiated care, especially in activities at home, avoiding possible falls and encouraging certain physical exercises. de Kam et al. 31 showed that exercise has positive effects on important predictors for falls and fractures, such as muscle strength, balance, and bone mineral density.
This study has some limitations. The included studies present a small number of patients, different doses of zolpidem, different treatment periods, and different analysis dates. Also, the studies used heterogeneous tests for the estimation of balance and cognition performances, which is why it was not possible to perform the meta-analysis.
The future of clinical research on this topic should stick to new randomized clinical trials, standardizing the tests for cognition and balance performed on the elderly population with a bigger sample size, allowing, then, a quantitative analysis of future systematic reviews. Future studies will allow us to consider the use of medication, by calculating the number needed to treat (NNT) or harm (NNH) to find out if the effectiveness in controlling insomnia and quality of life really outweighs the risks of cognitive and balance disorders.
The results of this study demonstrate that there is no statistically significant difference between zolpidem (5, 6.25, 10, and 12.5 mg) and placebo regarding cognitive dysfunctions (memory, psychomotricity, processing, attention, concentration, and vision). However, related to balance dysfunctions, the comparison between zolpidem (5 and 10 mg) and placebo showed that most articles present a statistically significant difference in favor of placebo, demonstrating that this drug produces relevant balance dysfunctions.