Objective: This study presents an updated meta-analysis of the effects of benzodiazepines on cognitive functioning in long-term, current users of these agents, those who have recently withdrawn and on those who have successfully abstained following withdrawal. The study represents an update of the previous meta-analyses published by our group.

Method: A comprehensive search of the computerized databases Medline and PsycINFO was undertaken to identify studies that assessed the cognitive effects of benzodiazepines published up to 28 November 2016 (the date of the last update). Nineteen studies (eight studies published since the previous meta-analyses and 11 studies included in the previous studies) were included.

Results: The results of the analysis for current users revealed statistically significant, negative effects for the cognitive domains of working memory, processing speed, divided attention, visuoconstruction, recent memory, and expressive language. For those who had withdrawn and successfully abstained following withdrawal, deficits were observed for the domains of recent memory, processing speed, visuoconstruction, divided attention, working memory, and sustained attention.

Conclusions: The results of the study are important in that they corroborate the mounting evidence that a range of neuropsychological functions are impaired as a result of long-term benzodiazepine use, and that these are likely to persist even following withdrawal. The findings highlight the residual neurocognitive compromise associated with long-term benzodiazepine therapy as well as the important clinical implications of these results.

Background: Acute benzodiazepine withdrawal has been described, but literature regarding the benzodiazepine-induced neurological injury that may result in enduring symptoms and life consequences is scant.

Objective: We conducted an internet survey of current and former benzodiazepine users and asked about their symptoms and adverse life events attributed to benzodiazepine use.

Methods: This is a secondary analysis of the largest survey ever conducted with 1,207 benzodiazepine users from benzodiazepine support groups and health/wellness sites who completed the survey. Respondents included those still taking benzodiazepines (n = 136), tapering (n = 294), or fully discontinued (n = 763).

Results: The survey asked about 23 specific symptoms and more than half of the respondents who experienced low energy, distractedness, memory loss, nervousness, anxiety, and other symptoms stated that these symptoms lasted a year or longer. These symptoms were often reported as de novo and distinct from the symptoms for which the benzodiazepines were originally prescribed. A subset of respondents stated that symptoms persisted even after benzodiazepines had been discontinued for a year or more. Adverse life consequences were reported by many respondents as well.

Limitations: This was a self-selected internet survey with no control group. No independent psychiatric diagnoses could be made in participants.

Conclusions: Many prolonged symptoms subsequent to benzodiazepine use and discontinuation (benzodiazepine-induced neurological dysfunction) have been shown in a large survey of benzodiazepine users. Benzodiazepine-induced neurological dysfunction (BIND) has been proposed as a term to describe symptoms and associated adverse life consequences that may emerge during benzodiazepine use, tapering, and continue after benzodiazepine discontinuation. Not all people who take benzodiazepines will develop BIND and risk factors for BIND remain to be elucidated. Further pathogenic and clinical study of BIND is needed.

9.3 Dependence Physical Dependence LOREEV XR (lorazepam) may produce physical dependence from continued therapy. Physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug. Abrupt discontinuation or rapid dosage reduction of benzodiazepines or administration of flumazenil, a benzodiazepine antagonist, may precipitate acute withdrawal reactions, including seizures, which can be life-threatening. Patients at an increased risk of withdrawal adverse reactions after benzodiazepine discontinuation or rapid dosage reduction include those who take higher dosages (i.e., higher and/or more frequent doses) and those who have had longer durations of use [see Warnings and Precautions ( 5.3 )]. To reduce the risk of withdrawal reactions, use a gradual taper to discontinue LOREEV XR (lorazepam) or reduce the dosage [see Dosage and Administration ( 2.4 ), Warnings and Precautions ( 5.3 )]. Acute Withdrawal Signs and Symptoms Acute withdrawal signs and symptoms associated with benzodiazepines have included abnormal involuntary movements, anxiety, blurred vision, depersonalization, depression, derealization, dizziness, fatigue, gastrointestinal adverse reactions (e.g., nausea, vomiting, diarrhea, weight loss, decreased appetite), headache, hyperacusis, hypertension, irritability, insomnia, memory impairment, muscle pain and stiffness, panic attacks, photophobia, restlessness, tachycardia, and tremor. More severe acute withdrawal signs and symptoms, including life-threatening reactions, have included catatonia, convulsions, delirium tremens, depression, hallucinations, mania, psychosis, seizures and suicidality. Protracted Withdrawal Syndrome Protracted withdrawal syndrome associated with benzodiazepines is characterized by anxiety, cognitive impairment, depression, insomnia, formication, motor symptoms (e.g., weakness, tremor, muscle twitches), paresthesia, and tinnitus that persists beyond 4 to 6 weeks after initial benzodiazepine withdrawal.

Patients at an increased risk of withdrawal adverse reactions after benzodiazepine discontinuation or rapid dosage reduction include those who take higher dosages (i.e., higher and/or more frequent doses) and those who have had longer durations of use [see Warnings and Precautions (5.3) ]. To reduce the risk of withdrawal reactions, use a gradual taper to discontinue Xanax (alprazolam) or reduce the dosage [see Dosage and Administration (2.3), Warnings and Precautions (5.3) ]. Acute Withdrawal Signs and Symptoms Acute withdrawal signs and symptoms associated with benzodiazepines have included abnormal involuntary movements, anxiety, blurred vision, depersonalization, depression, derealization, dizziness, fatigue, gastrointestinal adverse reactions (e.g., nausea, vomiting, diarrhea, weight loss, decreased appetite), headache, hyperacusis, hypertension, irritability, insomnia, memory impairment, muscle pain and stiffness, panic attacks, photophobia, restlessness, tachycardia, and tremor. More severe acute withdrawal signs and symptoms, including life-threatening reactions, have included catatonia, convulsions, delirium tremens, depression, hallucinations, mania, psychosis, seizures, and suicidality. Protracted Withdrawal Syndrome Protracted withdrawal syndrome associated with benzodiazepines is characterized by anxiety, cognitive impairment, depression, insomnia, formication, motor symptoms (e.g., weakness, tremor, muscle twitches), paresthesia, and tinnitus that persists beyond 4 to 6 weeks after initial benzodiazepine withdrawal.

In the United States, more than 30 million adults have reported taking a benzodiazepine within the past year. Misuse-use of a drug in a way that a doctor did not direct-accounts for 17.2% of all benzodiazepine use. Family physicians face challenges when balancing the patient's perceived benefits of benzodiazepines with known risks and lack of evidence supporting their use. Benzodiazepines cause significant central nervous system-related adverse effects including sedation, confusion, memory loss, depression, falls, fractures, and motor vehicle crashes. Factors that increase the risk of adverse effects and misuse are other substance use disorders, using concomitant central nervous system medications, and central nervous system or pulmonary diseases. Compared with intermittent use, chronic daily use in older adults is associated with a higher risk of falls, fractures, hospitalizations, and death. Withdrawal symptoms such as anxiety, sleep disturbances, and agitation are common and often prolonged. Adjunctive treatment with antiepileptics, antidepressants, and pregabalin has been shown to lessen withdrawal symptoms. Deprescribing benzodiazepines for patients who use them chronically should be individualized with slow tapering over weeks to months, or longer, to minimize the intensity of withdrawal symptoms. Incorporating behavioral interventions, such as cognitive behavior therapy, improves deprescribing outcomes.

The main disadvantages and dose-dependent side effects of benzodiazepines are drowsiness, lethargy, fatigue, excessive sedation, stupor, “hangover effects” the next day, disturbances of concentration and attention, development of dependence, symptom rebound (i.e., recurrence of the original disorder, most commonly a sleep disorder) after discontinuation, and hypotonia and ataxia. Benzodiazepines can seriously impair driving ability and are associated with increased risks of traffic accidents, as well as falls and fractures.

Patients with myasthenia gravis, ataxia, the sleep apnea syndrome, chronic respiratory insufficiency, spinal and cerebellar ataxia, angle-closure glaucoma, or acute CNS-depressant intoxication should not receive treatment with this class of drugs. Paradoxical reactions are not uncommon in older patients (>65 years of age). Psychomotor retardation and cognitive dysfunction (memory loss, lack of concentration, and attention deficits) may occur. These drugs are not recommended for the treatment of insomnia, agitation, or delirium in the elderly and, if prescribed in this population, should be restricted to short-term use. Their amnestic effects can result in memory gaps, especially at higher doses. An association of long-term benzodiazepine use with brain atrophy and dementia is controversial.

Purpose: Published evidence on the relationship between benzodiazepine exposure and altered cognition in the geriatric population is reviewed.

Summary: Benzodiazepines constitute one of the most commonly prescribed medication classes and are used primarily for management of anxiety and insomnia. Despite strong recommendations based on high-quality evidence warning of the potential cognitive adverse effects of benzodiazepine use, particularly in patients 65 years of age or older, published literature suggests that a substantial proportion of the U.S. geriatric population use these medications in a chronic fashion. The body of evidence suggesting that benzodiazepine use may be a modifiable risk factor for dementia continues to grow. Evidence exists to suggest that benzodiazepine use in the elderly population is associated with cognitive decline, dementia, and Alzheimer's disease, although evidence regarding the correlation between benzodiazepine use and dementia is conflicting; the more recent studies in this area have focused on eliminating causation bias. Pharmacists in a variety of settings can educate patients and assist providers in selecting an appropriate medication regimen for anxiety or insomnia that is tailored to each elderly patient's needs and takes into account the immediate and long-term safety of the patient.

Conclusion: Investigations of the association between benzodiazepine therapy and cognitive decline in elderly patients have yielded mixed findings. Stronger links have emerged from studies examining longer- rather than shorter-acting benzodiazepines, longer rather than shorter durations of use, or earlier rather than later exposure. Questions remain about causality and the impact of confounders on study interpretation.