What are the side effects of benzodiazepines (BZDs)?

Side Effects of Benzodiazepines

Benzodiazepines cause cognitive impairment, reduced mobility, falls, fractures, addiction, and respiratory depression, with particularly severe risks in older adults including increased mortality. 1

Neurological and Cognitive Effects

Central nervous system depression is the hallmark adverse effect of benzodiazepines, manifesting through multiple mechanisms:

• Cognitive impairment including memory deficits, confusion, and impaired concentration occurs commonly with benzodiazepine use 1
• Sedation and reduced coordination are dose-related effects that compromise complex skills such as driving 2, 3
• Psychomotor impairment can exceed that seen with blood alcohol levels of 0.05 g% 3
• Amnesia is a documented adverse effect, particularly with high-potency agents 4
• Paradoxical reactions including agitation, rage, irritability, aggressive or hostile behavior, and delirium can occur, though rarely 4, 5
• Thermal dysregulation can manifest as part of CNS depression, with benzodiazepines inhibiting shivering and affecting thermoregulation 6

Physical Safety Risks

Falls and fractures represent major morbidity concerns, particularly in vulnerable populations:

• Reduced mobility and unsafe driving skills are well-documented consequences 1
• Decline of functional independence occurs with chronic use 1
• Ataxia, nystagmus, and slurred speech appear with high doses, representing classical CNS-depressant features 3
• Impaired divided attention skills and increased reaction times compromise safety 3

Respiratory and Cardiovascular Effects

Respiratory depression is a serious and potentially life-threatening adverse effect:

• Synergistic respiratory depression occurs when benzodiazepines are combined with opioids or other CNS depressants 7
• Combining benzodiazepines with Z-drugs (zolpidem) significantly increases respiratory depression risk and should be avoided, especially in elderly patients 7
• Tachycardia, chest pain, and hyperventilation have been reported in clinical trials 4

Dependence and Withdrawal

Physical dependence develops from continued therapy, even at therapeutic doses, creating significant withdrawal risks:

• Withdrawal syndrome is characterized by sleep disturbance, irritability, increased anxiety, panic attacks, hand tremor, sweating, difficulty concentrating, nausea, weight loss, palpitations, headache, muscular pain and stiffness, and perceptual changes 8
• Severe withdrawal reactions include seizures, delirium tremens, hallucinations, psychosis, and suicidality, which can be life-threatening 9
• Approximately one-third of long-term users (beyond 6 months) experience withdrawal symptoms when attempting to discontinue 2
• Protracted withdrawal syndrome can persist for weeks to more than 12 months, characterized by anxiety, cognitive impairment, depression, insomnia, motor symptoms, paresthesia, and tinnitus 9
• Abrupt discontinuation or rapid dosage reduction precipitates acute withdrawal reactions; gradual tapering is essential 9

Abuse and Addiction Potential

Benzodiazepines are Schedule IV controlled substances with significant abuse potential:

• Abuse and misuse may lead to addiction, even when taken as prescribed 9
• Polysubstance abuse is common, with benzodiazepines frequently combined with opioids, alcohol, and illicit substances 9, 10
• Death is more often associated with polysubstance use, especially benzodiazepines with other CNS depressants 9
• Tolerance develops to therapeutic effects, though little tolerance develops to amnestic reactions and cognitive impairments 9

Psychiatric and Behavioral Effects

Psychiatric adverse effects range from common to severe:

• Depression has been reported, with increased suicide risk among untreated panic disorder patients taking benzodiazepines 4
• Anxiety, fatigue, and irritability are common discontinuation-emergent symptoms 4
• Confusional states, depersonalization, and derealization occur during treatment and withdrawal 4, 8
• Patients with borderline personality disorder or history of violent behavior may be at increased risk for adverse behavioral effects 4

Gastrointestinal and Metabolic Effects

• Nausea, vomiting, and diarrhea are common adverse effects 4
• Weight changes (both gain and loss) occur frequently 4
• Decreased appetite and salivation are reported 4

Special Population Risks

Older adults face disproportionate harm from benzodiazepines:

• Advanced age or frailty increases sensitivity to all benzodiazepine effects 6
• Five-fold increase in memory loss, confusion, and disorientation compared to placebo in older patients 1
• Three-fold increase in dizziness, loss of balance, or falls in elderly users 1
• Four-fold increase in residual morning sedation affecting next-day function 1
• High potency, long-acting, or prolonged use is considered high risk by Beers criteria 1

Long-Term and Serious Adverse Effects

Observational data suggest associations with serious outcomes, though causality requires careful interpretation:

• Increased all-cause mortality has been associated with anxiolytic and hypnotic drug use 1
• Association with dementia, major injuries, and possibly cancer has been reported 1
• Hepatic effects including elevated liver enzymes, elevated bilirubin, hepatitis, and hepatic failure have been reported post-marketing 4
• Severe dermatologic reactions including Stevens-Johnson syndrome and angioedema are rare but serious 4

Clinical Pitfalls and Monitoring

FDA warnings emphasize next-morning impairment and driving risks:

• Drugs taken at bedtime remain at levels high enough to interfere with morning driving, particularly in women and older/debilitated adults 1
• Dose reduction is advised in these populations 1
• Monitoring body temperature is particularly important during initial treatment phases 6
• Current consensus guidelines advise short-term use only 1