What are the adverse effects of long-term use of Zolpidem (zolpidem tartrate)?

From the Guidelines

Long-term use of zolpidem can lead to several adverse effects, including tolerance and dependence, cognitive impairments, complex sleep behaviors, and an increased risk of falls and fractures, particularly in older adults. The most concerning adverse effects of long-term zolpidem use are:

• Development of tolerance and dependence, where higher doses are needed to achieve the same sleep-inducing effect and withdrawal symptoms occur when stopping the medication 1
• Cognitive impairments, including memory problems, confusion, and impaired coordination 1
• Complex sleep behaviors like sleep-walking, sleep-eating, or even sleep-driving without full awareness 1
• Increased risk of falls and fractures, particularly in older adults, as well as potential mood changes including depression 1
• Loss of effectiveness over time, making insomnia worse 1 For these reasons, zolpidem is generally recommended only for short-term use (typically 2-4 weeks) 1. If you're currently taking zolpidem long-term, do not stop abruptly; instead, work with your healthcare provider to develop a gradual tapering schedule to minimize withdrawal effects 1. It's essential to weigh the benefits and harms of zolpidem use, considering the potential risks and the limited evidence on its long-term efficacy and safety 1. Observational studies have suggested that hypnotic drugs, including zolpidem, may be associated with infrequent but serious adverse effects, such as dementia, serious injury, and fractures 1. The FDA has approved pharmacologic therapy for short-term use (4 to 5 weeks), and patients should not continue using the drugs for extended periods 1. In conclusion, while zolpidem may improve short-term global and sleep outcomes for adults with insomnia disorder, its long-term use is associated with significant adverse effects, and its use should be carefully monitored and limited to short-term treatment.

From the FDA Drug Label

During longer-term treatment (28 to 35 nights) with zolpidem at doses up to 10 mg, the most commonly observed adverse reactions associated with the use of zolpidem and seen at statistically significant differences from placebo-treated patients were dizziness (5%) and drugged feelings (3%) Adverse Reactions Observed at an Incidence of ≥1% in Controlled Trials The following table was derived from results of three placebo-controlled long-term efficacy trials involving zolpidem tartrate. These trials involved patients with chronic insomnia who were treated for 28 to 35 nights with zolpidem at doses of 5,10, or 15 mg Table 2: Incidence of Treatment-Emergent Adverse Experiences in Placebo-Controlled Clinical Trials Lasting up to 35 Nights (percentage of patients reporting)

The adverse effects of long-term use of Zolpidem (zolpidem tartrate) include:

• Dizziness (5%)
• Drugged feelings (3%)
• Drowsiness (8%)
• Lethargy (3%)
• Lightheadedness (2%)
• Depression (2%)
• Abnormal dreams (1%)
• Amnesia (1%)
• Sleep disorder (1%)
• Diarrhea (3%)
• Abdominal pain (2%)
• Constipation (2%)
• Sinusitis (4%)
• Pharyngitis (3%)
• Rash (2%) 2

Note that the long-term use of zolpidem is associated with a range of adverse effects, and the incidence of these effects may vary depending on the dose and duration of treatment. 2

From the Research

Adverse Effects of Long-Term Use of Zolpidem

• The long-term use of zolpidem has been associated with various adverse effects, including an increased risk of falls in hospitalized patients with an OR of 4.28 (P <0.001) 3.
• The relative risk (RR) for hip fractures in patients taking zolpidem was described as 1.92 (95% CI 1.65-2.24; P<0.001), with hip fractures being the most commonly seen 3.
• Central nervous system (CNS)-related adverse effects, such as confusion, dizziness, and daytime sleepiness, have been reported in a majority (80.8%) of patients taking zolpidem 3.
• Zolpidem use has been linked to an increased risk of suicide attempts and completion, with an OR of 2.08 (95% CI 1.83-2.63) 3.
• Seizures have been reported following the withdrawal of zolpidem, with most cases occurring in patients taking daily dosages of around 450-600mg/day 3, 4.
• Rebound insomnia has been a concern with zolpidem use, with sleep onset latency significantly increased on the first night after stopping zolpidem (13.0 minutes; 95% CI 4.3-21.7; P<0.01) 3.

Special Considerations

• Women have been found to have a significantly higher serum zolpidem concentration than men, which may increase the risk of adverse effects 3, 5.
• The dose of zolpidem should be adjusted in elderly patients due to their slower drug metabolism 3, 6.
• Zolpidem has a lower incidence of residual daytime sleepiness and risk of falls compared to other hypnotics, making it a reasonable choice for therapy in some patients 3, 6.
• The FDA has classified zolpidem as a category C drug due to adverse outcomes seen in animal fetal development, and its use during pregnancy should be carefully considered 3.

Pharmacological Considerations

• Zolpidem is a non-benzodiazepine hypnotic agent with a rapid onset of action and short half-life, which may contribute to its efficacy and safety profile 6, 7.
• The extended-release formulation of zolpidem has been developed to extend the duration of hypnotic activity while minimizing the risk of residual next-day effects 7.
• The risk of adverse reactions to zolpidem may be increased by concomitant administration of other drugs that inhibit cytochrome P450 (CYP) isoenzymes 5.