Higher-Dose Uses of Zolpidem Will Increase the Subsequent Risk of Developing Benign Brain Tumors

The baseline demographic and clinical characteristics of the patients in the two cohorts are presented in Table 1. The mean (standard deviation) ages of patients in the zolpidem and non-zolpidem cohorts were 53.2 (16.0) and 53.6 (16.4) years, respectively. Of the 37,810 patients in the zolpidem cohort, some had a medicine history for stroke (9.38%), dementia (3.27%), epilepsy (1.70%), head injury (9.65%), and brain CT or MRI examinations (7.52%).

Overall, during the follow-up period, 147 of the 37,810 patients in the zolpidem cohort experienced a BBT. In addition, the zolpidem cohort (66.7 per 100,000 person-years) had a higher incidence of BBTs compared with the non-zolpidem cohort (50.2 per 100,000 person-years; hazard ratio=1.35, 95% CI=0.97–1.87), but this was not significant. There was a specifically higher incidence of BBTs for elderly participants for both cohort (≥50 years; 76.1 versus 62.5 per 100,000 person-years; Table 2). Regarding the results of the log-rank test and the cumulative incidence curve of BBTs (Figure 1), the risk of BBT was higher in the zolpidem cohort than that in the non-zolpidem cohort (log-rank, p=0.06). Conversely, taking zolpidem or not was not associated with a risk of MBTs (Table 2).

Moreover, associations between zolpidem dosage and brain tumor risk were analyzed (Table 3). The most significant risk of BBTs occurred in patients with zolpidem exposure ≥520 mg/years (hazard ratio=1.85, 95% CI=1.21–2.82). However, a significant relationship between zolpidem dosage and MBT risk was not observed (hazard ratio=0.50, 95% CI=0.05–5.51 for <520 mg/year; hazard ratio=2.00, 95% CI=0.18–22.1 for ≥520 mg/year).

Zolpidem is a short-acting hypnotic drug that binds at the benzodiazepine binding site on specific GABA receptors and enhances inhibitory neurotransmission.^11,12 Common adverse side effects of zolpidem use include nausea or vomiting, amnesia, headaches, hallucinations, short-term memory loss, and sleepwalking.¹³ The results of this population-based study indicated that zolpidem use also significantly increased the risk of subsequently developing BBT. The risk of developing BBT was higher at older ages (≥50 y) and higher zolpidem dosages (≥520 mg/year) in the zolpidem cohort. Tables 2 and 3 present the findings that should be shared with medical practitioners because these results might influence the long-term prescription of zolpidem, especially in the elderly population. We could not find an increase in the risk of developing MBTs, which probably is because of the small number of patients with MBTs in this study. Additionally, MBTs include metastatic and primary lesions, which could confound the mechanistic relationship of the results.

One possible explanation for the results is that patients with sleep disorders have greater opportunities of undergoing imaging studies; therefore, a greater probability exists for diagnosing brain tumors in these groups. Table 1 showed that patients taking zolpidem had higher probability of undergoing brain CT or MRI examinations than did the non-zolpidem group. Another explanation is that slow-growing BBTs are typically accompanied with dizziness, seizures, sleep disorders, and cognitive problems, which are frequently initially treated with hypnotic drugs before a tumor diagnosis is made.^14,15 To rule out this reverse causality, which implies that patients who are already at risk of BBTs might have a greater tendency of using zolpidem than those not at risk of BBTs, we used the Kaplan-Meier method without adjusting for sex, age, and comorbidities. Figure 1 indicates that the risk of BBT increases with the length of time of zolpidem use; thus, reverse causality appeared unlikely.

The most frequently reported BBTs are meningiomas (a tumor of the meninges, comprising 24.0% of all brain tumors), and the most frequently reported MBTs are glioblastomas (a tumor of the neuroepithelial tissue, 22.6%). This indicates that, in most instances, BBTs and MBTs derive from different histologies and have different genetic and molecular expressions.^16–18 Zolpidem enhances inhibitory neurotransmission by interacting with the GABA receptor-coupled chloride channel. Apart from their role as an inhibitory neurotransmitter, GABA receptors may regulate various stages of cell proliferation and differentiation in the brain and periphery and thus may be involved in tumor growth by various means.^19,20 Furthermore, zolpidem has been reported to promote viral infections, which might suppress immune function and induce the development of BBTs.²¹ However, the potential mechanisms of hypnotic drugs and brain tumor growth or suppression still remain unclear and controversial. For instance, Gourdeau et al. found that ECO-4601, a benzodiazepine receptor ligand, was shown to bind the peripheral but not the central benzodiazepine receptor and inhibited the growth of CNS tumor cell lines.²² Richardson et al. found benzodiazepine-GABA(A) receptor binding is very low in dysembryoplastic neuroepithelial tumors, a benign brain tumor.²³ Recently, Bode et al. reported that knockdown the peripheral type benzodiazepine receptor (now known as translocator protein) and exposure to translocator protein ligands enhances brain tumor proliferation in an animal model.²⁴ Those implied that the change of benzodiapepine binding affinity by zolpidem and other drugs with similar CNS effects might play a role in the neoplastic growth of the brain.

One strength of this study is the nationwide population-based design and representativeness. However, this study has limitations. First, only claims data were available in the NHIRD; other detailed information, such as smoking habits, alcohol consumption, body mass index, socioeconomic status, and family history of cancer, was not provided by the NHIRD. These might be risk factors of brain tumors and could potentially be associated with zolpidem use. However, because the NHIRD contains information regarding nearly the entire population in Taiwan and the Taiwan National Health Insurance reimbursement policy is identical for all patients, it is unlikely that these factors would affect the prescription of zolpidem. Second, the results derived from a cohort study are typically less accurate than those obtained from randomized control trials because a cohort study design is subject to numerous biases related to confounding adjustment. Despite the meticulous study design with adequate control of confounding factors by propensity score matching, a key limitation is any remaining bias regarding unmeasured or unknown confounders. Third, we could follow the codes for zolpidem prescription by administrative billing in the Taiwan National Health Insurance claims but we were unable to contact the patients directly regarding their exact doses of zolpidem use because their identification numbers were anonymous. Finally, prescriptions for these drugs before 1996 were not included in our analysis, which could have caused underestimations of cumulative dosages and might weaken the observed association. However, zolpidem prescription and tumor diagnosis data were exceptionally reliable.

In conclusion, the results of this population-based, retrospective cohort study showed a significant increase in BBT risk associated with zolpidem use. Additional studies including randomized control trials with the same findings are required before any conclusions can be confirmed.

This work was supported by the study projects (DMR-102-023 and DMR-103-020) in our hospital; Taiwan Ministry of Health and Welfare Clinical Trial and Research Center of Excellence (MOHW103-TDU-B-212-113002); Health and welfare surcharge of tobacco products, China Medical University Hospital Cancer Research Center of Excellence (MOHW103-TD-B-111-03, Taiwan); and International Research-Intensive Centers of Excellence in Taiwan (I-RiCE) (NSC101-2911-I-002-303). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. No additional external funding was received for this study.