What are the side effects of benzodiazepines in older adults or individuals with a history of substance abuse?

Benzodiazepine Side Effects

Benzodiazepines cause cognitive impairment, falls, fractures, respiratory depression, and addiction, with particularly severe risks in older adults and individuals with substance abuse history who should rarely receive these medications. 1, 2

Core Adverse Effects in All Populations

Neurological and Cognitive Impairment

• Cognitive impairment including memory deficits, confusion, impaired concentration, and decreased attention occurs commonly with benzodiazepine use 3, 2
• Drowsiness, fatigue, and sedation are the most commonly reported side effects 4
• Ataxia, muscle weakness, and reduced mobility significantly impair physical function 1, 4
• Dysarthria, slurred speech, tremor, and vertigo can occur during treatment 4
• Antegrade amnesia may occur even at therapeutic dosages, with risk increasing at higher doses 4

Physical Safety Risks

• Unsafe driving skills persist into the morning after bedtime dosing, particularly in women and older adults, requiring dose reduction in these populations 2, 4
• Blurred vision, diplopia, and dizziness impair visual function 4
• Gastrointestinal disturbances including constipation, nausea, and changes in salivation (dry mouth or hypersalivation) 4

Psychiatric and Paradoxical Reactions

• Paradoxical reactions including stimulation, restlessness, acute hyperexcited states, anxiety, agitation, aggressiveness, irritability, rage, hallucinations, psychoses, and delusions can occur, particularly in children and elderly patients 4
• Depression, confusion, and inappropriate behavior have been reported and warrant immediate discontinuation 4
• Sleep disturbances, insomnia, and nightmares may paradoxically worsen 4

Cardiovascular and Other Effects

• Hypotension can occur 4
• Urinary retention or incontinence and changes in libido 4
• Skin reactions have been reported 4
• Elevated transaminases and alkaline phosphatase warrant periodic liver function monitoring during long-term therapy 4

Critical Risks in Older Adults

Dramatically Increased Morbidity and Mortality

• Five-fold increase in memory loss, confusion, and disorientation compared to placebo in older patients 2
• Three-fold increase in falls, dizziness, and loss of balance in elderly users 2
• Four-fold increase in residual morning sedation affecting next-day function 2
• Falls and fractures represent the most serious physical safety risk, with increased risk in those taking concomitant sedatives including alcohol 1, 4
• Increased all-cause mortality has been associated with anxiolytic and hypnotic drug use in older adults 2
• Association with dementia, major injuries, and possibly cancer has been reported 2

Age-Related Vulnerability

• Advanced age or frailty increases sensitivity to all benzodiazepine effects due to decreased clearance and accumulation of active metabolites 3, 2
• Thermal dysregulation can manifest as part of CNS depression, with benzodiazepines inhibiting shivering and affecting thermoregulation 2
• Decline of functional independence occurs with chronic use 1, 2
• The American Geriatrics Society Beers Criteria strongly recommends avoiding benzodiazepines in patients aged 65 and older, particularly high-potency, long-acting, or prolonged use 1, 5

Severe Risks in Substance Abuse History

Addiction and Dependence Potential

• Benzodiazepines should be used with extreme caution in patients with a history of alcohol or drug abuse due to high addiction potential 4, 6
• Even taking benzodiazepines as prescribed exposes users to risks of abuse, misuse, and addiction, which can lead to overdose and death 4
• Benzodiazepines are often sought by individuals who abuse drugs and other substances, and by individuals with addictive disorders 4
• Tolerance develops with chronic use as GABA-A receptors undergo adaptive changes, leading to physical dependence and withdrawal risk upon discontinuation 3

Polysubstance Use Dangers

• Death is more often associated with polysubstance use, especially benzodiazepines with other CNS depressants such as opioids and alcohol 4
• Synergistic respiratory depression occurs when combined with opioids, with potentially fatal consequences 2, 4
• Combining benzodiazepines with Z-drugs (zolpidem) significantly increases respiratory depression risk and should be avoided 2

Severe Abuse-Related Adverse Effects

• Delirium, paranoia, suicidal ideation and behavior, seizures, coma, breathing difficulty, and death have occurred with benzodiazepine abuse and misuse 4
• Abdominal pain, amnesia, anorexia, anxiety, aggression, confusion, depression, disinhibition, disorientation, euphoria, impaired concentration and memory, irritability, muscle pain, slurred speech, tremors, and vertigo occur with abuse 4

Dependence and Withdrawal Syndrome

Physical Dependence Development

• Physical dependence develops from continued therapy, manifested by withdrawal signs and symptoms after abrupt discontinuation or significant dose reduction 4
• Abrupt discontinuation or rapid dosage reduction can precipitate acute withdrawal reactions, including seizures, which can be life-threatening 4

Acute Withdrawal Symptoms

• Acute withdrawal signs include abnormal involuntary movements, anxiety, blurred vision, depersonalization, depression, derealization, dizziness, fatigue, gastrointestinal reactions (nausea, vomiting, diarrhea, weight loss), headache, hyperacusis, hypertension, irritability, insomnia, memory impairment, muscle pain and stiffness, panic attacks, photophobia, restlessness, tachycardia, and tremor 4
• More severe acute withdrawal reactions include catatonia, convulsions, delirium tremens, hallucinations, mania, psychosis, seizures, and suicidality 4

Protracted Withdrawal Syndrome

• Protracted withdrawal syndrome characterized by anxiety, cognitive impairment, depression, insomnia, formication, motor symptoms (weakness, tremor, muscle twitches), paresthesia, and tinnitus persists beyond 4-6 weeks after initial withdrawal 4
• Protracted withdrawal symptoms may last weeks to more than 12 months 4

Critical Clinical Pitfalls

• Current consensus guidelines advise use of benzodiazepines solely on a short-term basis due to the multitude of serious consequences 1, 2
• Around half of patients prescribed benzodiazepines are treated continuously for at least 12 months, a practice not recommended by clinical guidelines 5
• In debilitated patients, dosage should be limited to the smallest effective amount (2-2.5 mg once or twice daily initially) to preclude development of ataxia or oversedation 4
• Patients should be cautioned against engaging in hazardous occupations requiring complete mental alertness, such as operating machinery or driving 4
• Simultaneous ingestion of alcohol and other CNS-depressant drugs must be avoided during benzodiazepine therapy 4
• Periodic blood counts and liver function tests are advisable during long-term therapy due to isolated reports of neutropenia and jaundice 4