Incidence of Adverse Effects and Misuse of Zolpidem

Abstract

Study Objectives:

Zolpidem is a widely prescribed medication for treating insomnia due to its effectiveness as a sedative-hypnotic. This study aimed to estimate the incidence of potential adverse effects associated with the use and misuse of zolpidem.

Methods:

Retrospective cohort study. Participants were selected from consumers who had purchased zolpidem in a commercial pharmacy in Brazil and submitted an interviewed. Descriptive analysis was used to present the results. Pearson‘s chi-square tests were used to compare adverse reactions to zolpidem with categorical variables, and Student‘s t-tests were used to compare means. The significance level adopted was 5%.

Results:

The study involved 65 participants, with a mean age of 52.7 years, 76.9% of whom were women. Of the total sample, 69.2% used zolpidem for the treatment of long-term insomnia, and 77.4% used it continuously. Among the interviewees, 55.4% reported experiencing adverse reactions, with amnesia, insomnia, and sleepwalking being the most reported. A statistically significant association was found between the occurrence of adverse reactions and continuous use (P value = 0.048), as well as among those with lower mean age (P value = 0.042).

Conclusion:

Despite being a prescription-controlled medication, zolpidem was used excessively and inappropriately in the studied sample. Given the high prevalence of adverse effects identified in this study, the risk/benefit ratio of pharmacological treatments for insomnia warrants careful evaluation during prescription and dispensing. Incidence of adverse effects and misuse of zolpidem.

Introduction

Insomnia is a sleep disorder that affects a large portion of the population. At any point in life, an individual may experience some form of sleep disorder, but this is more common in older adults; the increase in comorbidities, psychiatric disorders, and the aging process itself can be factors that exacerbate sleep disorders.^1,2 Many individuals seek medical or pharmacological solutions to improve their sleep quality, although non-pharmacological interventions should be considered first. Despite the availability of alternative options, the use of sleep-inducing medications is on the rise. ³

In the treatment of insomnia, benzodiazepine receptor agonists are used. Among the classes utilized are benzodiazepine anxiolytics (clonazepam, lorazepam, and flunitrazepam) ⁴ and non-benzodiazepine hypnotics with selective GABA-A receptor agonist activity (zolpidem, zopiclone, and zaleplon), which are the first choice for the treatment of short-term insomnia. ⁵ Additionally, antidepressants, antihistamines, antipsychotics, and so-called natural compounds are also sometimes used in the treatment of insomnia. ⁵

One of the most used pharmacological treatments for sleep disorders in Brazil and worldwide is zolpidem. ⁶ It is a short-acting sedative/hypnotic that acts on the alpha-1 receptor with a more selective action and theoretically fewer adverse effects. ⁷ This class of medication is prescribed under strict control and sold only with a prescription. ⁸ However, a study conducted in the United States between 2011 and 2013 revealed that zolpidem was the psychoactive drug most associated with emergency service visits due to adverse drug event. ⁹

Zolpidem is available in doses of 5, 6.25, 10, and 12.5 mg. It comes in pharmaceutical forms such as tablets, sublingual tablets, orodispersible tablets, coated tablets, extended-release tablets, and effervescent tablets. After oral administration, zolpidem plasma levels peak within 1 to 3 hours. Plasma levels can be amplified by up to 2 hours when used in its extended-release form. On average, its half-life is 2.4 hours. ¹⁰

In Brazil, various formulations are marketed: 5mg in the form of a sublingual tablet, 10 mg as a coated tablet, and 6.25 mg and 12.5 mg as extended-release tablets. ⁶ The clinical indication is intended for the short-term treatment of occasional, transient, or long-term insomnia. For occasional insomnia, it may be used for 2 to 5 days; and for transient insomnia, from 2 to 3 weeks. Prolonged use of this medication can lead to dependency after 4 weeks, and abrupt discontinuation of the drug can cause rebound insomnia. Moreover, prolonged use of this medication can lead to dizziness, retrograde amnesia, headache, hallucinations, reality distortions, bone fractures as a result of falls, sleepwalking, behavioral changes, worsening depression, and suicidal attempt.^{11 -13} In Brazil, there is no standardization or limitation regarding the doses prescribed for women or men. According to the Federal Drug Administration (FDA), the recommended dose for women is 5mg because they metabolize zolpidem more slowly than men.^14,15 Recently, in 2024, the Brazilian Health Regulatory Agency (ANVISA), equivalent to the FDA in the United States, restricted the prescription of zolpidem to registered physicians to enhance the control of its prescription, sale, and use. ¹⁶

Despite the recommendation not to exceed 4 weeks, the use of zolpidem has become common in continuous prescriptions, with a trend toward excessive consumption. This raises concerns about the potential adverse effects due to prolonged use and overdosing of this drug.^6,17

Based on the above, this study aimed to estimate the incidence of potential adverse effects associated with the use and misuse of zolpidem.

Methods

The sample for this retrospective cohort study consisted of users from a busy commercial pharmacy in Brazil. Participants were selected from consumers who had purchased zolpidem at the study site between July and August 2023, provided they were aged 18 years or older, of both sexes, and agreed to participate in the study.

The users of the pharmacy in question, upon receiving the study medication, were invited to take part in the research. Consent was obtained through the signing of an Informed Consent Form. The interview was conducted using a printed questionnaire to gather information regarding the occurrence of adverse effects and the consumption of zolpidem. The questionnaire covered sociodemographic details (such as age, sex, race, education level, and marital status), specifics of zolpidem use (including the reason for use, dosage – 5mg, 6.25 mg, 10mg or 12.5 mg), quantity, timing, and duration of consumption, reported adverse effects experienced, and the medical specialty of the prescribing physician. We defined continuous use of zolpidem as when the participant reported daily use of the medication for more than 4 weeks, contrary to the recommendations in the medication package insert; and those who renewed their prescription every 60 days with a daily use indication.

The data obtained was entered into a spreadsheet created using Microsoft Excel® software. Statistical analysis was conducted using SPSS software version 21 (IBM, Armonk, New York, USA). Descriptive analysis was used to present the results. Pearson‘s chi-square test was used to compare zolpidem dosage and sex, as well as to assess the association between adverse reactions to zolpidem with categorical variables, such as sex, reason for use, dosage and length of use. Student‘s t-test was used to compare mean ages concerning the occurrence of adverse events related to zolpidem. The significance level adopted was 5%. This study was approved by the Research Ethics Committee of the University of Southern Santa Catarina, with approval number 6.091.016 on May 30, 2023, and amendment approval number 6.169.895 on July 7, 2023.

Results

The sample consisted of 65 participants, with a mean age of 52.7 (SD ± 14.6) years, ranging from a minimum age of 22 to a maximum age of 85 years. Table 1 presents the sociodemographic characteristics of the study participants.

Table 1.

Sociodemographic Characteristics of Zolpidem Users in Southern Santa Catarina, Brazil, 2023 (n=65).

Variable	n	%
Age
22-29	1	1.5
30-39	11	16.9
40-49	15	23.1
50-59	17	26.2
>60	21	32.3
Sex
Male	15	23.1
Female	50	76.9
Education
Elementary school	3	4.6
High school	21	32.3
College education	41	63.1
Skin color
White	64	98.5
Black	1	1.5
Marital status
Single	8	12.3
Married	43	66.2
Divorced	6	9.2
Widow	8	12.3
Specialty of the prescriber
Family physician	18	27.7
Neurologist	4	6.2
Pychiatrist	25	38.4
Other	18	27.7

Regarding the use of zolpidem, the reasons for use, dosage, quantity, and duration of medication use were evaluated and are presented in Table 2. The different zolpidem dosages were not associated with age, sex, duration of use, or the occurrence of adverse reactions (general or specific).

Table 2.

Characteristics of Zolpidem Use Among Users in Southern Santa Catarina, Brazil, 2023 (n=65).

Variable	n	%
Reason for use
Occasional insomnia	12	18.5
Transient insomnia	8	12.3
L-term insomnia	45	69.2
Dosage
5 mg	16	24.6
6.25 mg	2	3.1
10 mg	46	70.8
12.5 mg	1	1.5
Daily quantity
1	56	86.2
2	3	4.6
>2	2	3.1
Occasional use if needed	4	6.2
Length of use
First time	2	3.1
Occasional use if needed	12	18.5
Oingoing use	51	77.4

The average duration of zolpidem use ranged from 1 to 180 months, with a median of 36 months. Out of the 65 study participants, 36 (55.4%) reported experiencing adverse reactions to zolpidem, while 3 (4.6%) were unsure if they had any reactions. The adverse reactions reported can be viewed in Table 3.

Table 3.

Self-Reported Adverse Effects Among Zolpidem Users in Southern Santa Catarina, Brazil, 2023 (n=65).

Adverse reaction	n	%
Amnesia	18	27.7
Insomnia	15	23.1
Sleepwalking	11	16.9
Hallucinations	10	15.4
Mood changes	4	6.2
Headache	2	3.1
Depression	2	3.1
Dizziness	1	1.5
Other	6	9.2

Reported reactions include anxiety, fatigue, and increased appetite. When analyzing each specific adverse reaction, continuous use was positively associated with insomnia (P value = 0.016). The occurrence of hallucinations showed a trend of association with continuous zolpidem use (P value = 0.057). Psychiatrists (46.0%) were the specialists who most frequently prescribed zolpidem for continuous use, followed by general practitioners (26.0%). Continuous use was also more frequent in cases of chronic insomnia treatment (P value < 0.001). There was also no statistically significant difference between the participants‘ sex and the dose of zolpidem used (P value = 0.813).

Table 4 presents the association between the occurrence of adverse effects and demographic characteristics and zolpidem use.

Table 4.

Association Between the Occurrence of Adverse Effects and Demographic Characteristics and Zolpidem Use.

	Adverse effects n (%)
Variable	Yes	No	P value
Mean age (SD) †	49.4 (13.0)	56.8 (15.6)	0.042
Sex			0.855
Male	8 (53.3)	7 (46.7)
Female	28(56.0)	22 (44.0)
Reason for use			0.096
Occasional/transient insomnia	8 (40.0)	12 (60.0)
Chronic insomnia	28 (62.2)	17 (37.8)
Dosage*			0.565
Lower	11 (61.1)	7 (38.9)
Higher	25 (53.2)	22 (46.8)
Length of use			0.048
Occasional use if needed	5 (33.3)	10 (66.7)
Oingoing use	31(62.0)	19 (38.0)

^†Student‘s t-test.

^*Lower 5 to 6.25 mg; Higher 10 to 12.5 mg.

Discussion

In the studied sample, most zolpidem users were older adults, mainly women with higher education levels, white skin color, and who were married. Zolpidem was predominantly prescribed by psychiatrists. These characteristics can be attributed to several factors. For instance, zolpidem is not distributed in the basic pharmacy of the unified health system. The sample was gathered from a commercial pharmacy, which typically caters to clients with higher purchasing power, supplementary health insurance, and higher education. Furthermore, the municipality’s population is situated in southern Brazil, where individuals of white descent are prevalent.

Chronic insomnia may result in the continued use of medications when causal factors are not identified, and non-pharmacological treatments are not employed. Zolpidem is known as one of the most prescribed sedative-hypnotics globally due to its rapid onset and low incidence of adverse effects, ¹⁸ when used for short-term treatment. ¹⁹ However, despite its efficacy in improving patients‘ sleep, prolonged use of the drug can increase the risk of dependence and adverse effects, even at appropriate doses. ²⁰

This study highlights several frequently reported adverse reactions to zolpidem, such as amnesia, insomnia, sleepwalking, and hallucinations. These adverse reactions not only affect the patient‘s quality of life but can also demonstrate rebound effects (as insomnia) with prolonged use, potentially leading to serious physical and mental health consequences. ²¹ It is crucial to recognize that reactions to zolpidem may be underestimated due to the drug‘s impact on the central nervous system and challenges in obtaining accurate information from family members or caregivers. Furthermore, some participants in the study had been using the medication for over a decade, despite it being contraindicated according to the medication‘s label.

Edinoff et al ⁶ describe an association between the use of zolpidem and a higher risk of falls, fractures, and central nervous system damage, leading to cognitive impairments, such as memory issues, confusion, and dizziness. Inagaki and colleagues note that zolpidem can be linked to the development of adverse neuropsychiatric reactions, such as hallucinations/sensory distortion, amnesia, sleepwalking, and nocturnal eating. Additionally, women tend to have notably higher serum concentrations of zolpidem compared to men, and the adverse reactions that manifest are dose dependent. ²² However, in the present study, there was not sufficient power to detect differences between sexes regarding the incidence of adverse events or the prescribed dosage for men and women. Similarly, higher dosages were not associated with an increased occurrence of adverse events. Khan et al ¹⁷ have also identified a positive correlation between the use of zolpidem and suicidal ideation or suicide attempts.

In a recent review study by Crescenzo et al ¹⁸ assessing the effects of pharmacological therapy in managing acute and chronic insomnia, zolpidem was linked to a higher rate of discontinuations due to adverse effects compared to placebo. Nonetheless, in comparison to other medications like benzodiazepines, zolpidem is better tolerated, explaining its prevalent prescription and continuous use.^18,19

In the present study, a higher incidence of adverse events was observed among participants with a lower average age compared to those who did not report adverse reactions. No data was found to explain this difference, even when dosage and daily intake were analyzed. This may be related to a greater perception of reported adverse events compared to older adults.

Among these and other considerations, healthcare professionals, such as physicians, pharmacists, and others involved in dispensing zolpidem and associated medications, should prioritize rational drug use by assessing the risk/benefit of prescription and usage decisions through shared decision-making with the patient. To effectively manage insomnia, a multimodal strategy incorporating sleep hygiene, cognitive-behavioral therapy for insomnia (CBT-I) or brief behavioral therapy for insomnia (BBTI), and appropriate medication use should be implemented. ²⁰ Moreover, in Brazil, the National Health Surveillance Agency (ANVISA) has the VIGIMED tool for reporting adverse drug events. This tool assists healthcare professionals in understanding the risks associated with certain formulations used in clinical practice.

Among the limitations of the present study, the small sample size and the lack of observation of concurrent medication use stand out. These issues were due to challenges in accessing potential study participants, given the General Data Protection Law of the healthcare establishment, which led to a demand-based sampling approach. The small sample size may also have affected the analysis of factors associated with adverse reactions to zolpidem, compromising a more robust statistical analysis with greater study power. It is worth noting that there is limited research on zolpidem consumption in Brazil, highlighting the caution needed when deviating from recommended guidelines.

It can be concluded that zolpidem has been excessively and inappropriately used, despite being a prescription-controlled medication. Although insomnia is a significant disorder with serious consequences for the human body, healthcare professionals must carefully assess the risk/benefit ratio when prescribing and dispensing this drug, considering the high prevalence of adverse effects found in this study.

Conclusion

Based on the data from this study, it can be concluded that the incidence of self-reported adverse events among zolpidem users was 55.4%, and 76.9% were continuously using the drug beyond the 4-week period recommended. Among the reported adverse effects, amnesia, insomnia, sleepwalking, and hallucinations stood out, all of which have a direct impact on patients‘ quality of life. Additionally, the study highlights the emergence of rebound effects from prolonged use and the occurrence of severe adverse reactions that can significantly affect both physical and mental health.