What are the common side effects of benzodiazepines?

[NOTE: This article has been posted prior to peer review for use in an active research program. This content will be updated with a peer reviewed version as soon as it is available.]

The incidence of common and very common adverse events with placebo incidence subtracted is listed below.

Table 1: Common and very common adverse effects and the percentage of their incidence less placebo in manufacturers’ drug trials for benzodiazepines^1-8

The manufacturer prescribing information for diazepam (Valium) does not specify the incidence of adverse events but notes that the most commonly reported side effects were drowsiness, fatigue, muscle weakness, and ataxia.⁴ Similarly, the manufacturer prescribing information for lorazepam (Ativan) only lists the most frequent adverse reactions of sedation (15.9%), dizziness (6.9%), weakness (4.2%), and unsteadiness (3.4%).⁵

A 2019 meta-analysis of acute treatment of panic disorder sought to estimate the incidence of side effects associated with benzodiazepine use.⁹ The side effects more commonly reported in intervention arms compared to placebo were somnolence (29.0% vs 11.0%, Odds Ratio [OR] 4.59, p=0.03), decreased libido (14.6% vs 3.5%, OR 4.28, p<0.01), constipation (12.9% vs 5.4%, OR 2.52, p<0.01), memory problems (16.8% vs 7.2%, OR 2.11, p<0.01), and dry mouth (14.5% vs 9.3%, OR 1.54, p<0.01).

Discontinuation

In clinical trials conducted by manufacturers, the following percentages of patients discontinued therapy for clinical adverse experiences:

• Alprazolam: 17% (8% placebo)¹
• Clonazepam: 17% (9% placebo)³

The manufacturer information for triazolam notes that the adverse reactions leading to discontinuation included

coordination disorders, drowsiness, grogginess, somnolence, depression, restlessness, dizziness, lightheadedness, headache, nausea, visual disturbance, nervousness, abdominal distress, bladder trouble, aching limbs, backache, and blepharitis.⁸ The information for clobazam notes that adverse reactions leading to discontinuation included lethargy, somnolence, ataxia, aggression, fatigue, and insomnia.²

Continued use of benzodiazepines can lead to physical dependence which can in turn result in withdrawal symptoms, particularly with abrupt discontinuation.^1-8 Acute withdrawal symptoms include abnormal involuntary movements, anxiety, depersonalization, depression, derealization, dizziness, fatigue, gastrointestinal adverse reactions (e.g., nausea, vomiting, diarrhea, weight loss, decreased appetite), headache, hypertension, irritability, insomnia, memory impairment, muscle pain and stiffness, panic attacks, restlessness, sensory disturbances (e.g., auditory and visual hallucinations, blurred vision, hyperacusis, photophobia), tachycardia, and tremor. More severe withdrawal signs and symptoms, including life-threatening reactions, have included catatonia, convulsions, delirium tremens, hallucinations, mania, psychosis, seizures, and suicidality.

Protracted withdrawal symptoms lasting weeks to over a year have been reported with symptoms including anxiety, cognitive impairment, depression, insomnia, formication, motor symptoms (e.g., weakness, tremor, muscle twitches), paresthesia, and tinnitus.^1-8 However, because of the length that these symptoms have been reported to last, it’s difficult to know whether they are truly a result of withdrawal or potentially the re-emergence of symptoms the medication had been introduced to treat.

Severe withdrawal symptoms are very rare making it difficult to estimate incidence. An analysis of one hospital’s electronic records found that from 2009-2016, there were 82 reports of benzodiazepine withdrawal.¹⁰ Of these cases, 31 involved concurrent withdrawal from another drug (25 opioid, six ethanol). Among these cases, seven were admitted to the intensive care unit, although only two of these were withdrawing from benzodiazepines alone. Seizures occurred in eight cases.

Manufacturers recommend that when discontinuing a benzodiazepine, patients gradually reduce their dose if possible to reduce the risk of adverse effects.^1-8

References

1. Xanax (alprazolam) tablets [package insert]. Morgantown, WV: Viatris Specialty; 2023.
2. Onfi (clobazam) tablets [package insert]. Winchester, KY: Catalent Pharma Solution; 2024.
3. Klonopin (clonazepam) tablets [package insert]. Montgomery, AL: H2-Pharma; 2023.
4. Valium (diazepam) tablets [package insert]. Wixom, MI: Waylis Therapeutics; 2023.
5. Ativan (lorazepam) tablets [package insert]. Bridgewater, NJ: Bausch Health; 2023.
6. Doral (quazepam) tablets [package insert]. Atlanta, GA: Galt Pharmaceuticals; 2023.
7. Restoril (temazepam) tablets [package insert]. Webster Groves, MO: SpecGx; 2023.
8. Halcion (triazolam) tablets [pa ckage insert]. New York, NY: Pharmacia & Upjohn Co; 2023.
9. Quagliato LA, Cosci F, Shader RI, et al. Selective serotonin reuptake inhibitors and benzodiazepines in panic disorder: A meta-analysis of common side effects in acute treatment. J Psychopharmacol. Nov 2019;33(11):1340-1351. doi:10.1177/0269881119859372
10. Thornton SL, Whitacre J, Pallo N, Roberts N, Oller L. A Retrospective Review of Morbidity and Mortality Associated with Acute Benzodiazepine Withdrawal at a Midwestern Academic Medical Center. Kans J Med. 2021;14:77-79. doi:10.17161/kjm.vol1414653