An association between benzodiazepine use and occurrence
of benign
brain tumors
Tomor Harnod
a,b, Cheng-Li Lin
c,d, Fung-Chang Sung
c,d, Chia-Hung Kao
e,f,⁎
a Department of Neurosurgery, Buddhist Tzu Chi General Hospital, Hualien, Taiwan
b College of Medicine, Tzu Chi University, Hualien, Taiwan
c Management Offce for Health Data, China Medical University Hospital, Taichung, Taiwan
d Department of Public Health, China Medical University, Taichung, Taiwan
e Department of Nuclear Medicine and PET Center, China Medical University Hospital, Taichung, Taiwan
f Graduate Institute of Clinical Medical Science, School of Medicine, College of Medicine, China Medical University, Taiwan
1. Introduction
Benzodiazepines are a category of drug that is widely used to treat various neurological and psychiatric conditions such as seizures, agitation, insomnia, anxiety, alcohol dependence, and panic. The prevalence of benzodiazepine use ranges from 10% to 43% worldwide among the
aged population [1–5]. Meanwhile, benzodiazepines are also known to
have some adverse effects, such as nausea, vertigo, amnesia, ataxia, headache, drowsiness, confusion, or even tremor, which imply the possible neuro-toxicity in long-term or high-dose use of benzodiazepines.
Previous animal studies have revealed that benzodiazepine might increase
the risk of liver and breast cancer [6,7]. A survey conducted in
the United States found that the use of sleeping pills (most of which
are benzodiazepines) increased the risk of developing cancer [8]. We
published similar results from a retrospective cohort study conducted
in Taiwan in 2012 [9]. However, although there is a long history of
human beings modulating the central nervous system, the potential link between benzodiazepine use and subsequent brain tumor development remains unclear. This study was conducted using the Taiwan
nationwide population-based database. 2. Methods
2.1. Data sources
The National Health Insurance (NHI) program was initiated in Taiwan on March 1, 1995. By the end of 2009, approximately 99% of Taiwan's 23.74 million people were enrolled in the National Health
Insurance Research Database (NHIRD) [10]. The National Health
this study was obtained from a NHIRD sub-data set, which contains the longitudinal claim data of a cohort of 1,000,000 insurance enrollees randomly selected from all of the insured benefciaries. The NHIRD is one of the largest insurance databases in theworld, and previous studies
have shown the accuracy and high validity of ICD-9 codes' diagnoses stored in the database [11,12].
We used three data fles: the registry of
benefciaries, ambulatory care claims, and inpatient claims. The database provided confdential information such as patient identifcation
number, birthdate, sex, occupation, residential area, medications, and diagnostic codes in the format of the International Classifcation of Disease, Ninth Revision, ClinicalModifcation (ICD-9-CM).With approval from NHI and China Medical University, this study was exempted by the Institutional Review Board (CMU-REC-101-012).
2.2. Study participants
For the benzodiazepine cohort, we identifed 62,186 patients (mean
age = 47.4 years, SD = 14.1 years)who had been prescribed benzodiazepine for at least 2 months between January 1, 2000 and December
31, 2009. We defned the index date as the initial date of benzodiazepine treatment. We excluded patients with a history of benign brain
tumors and malignant brain tumors diagnosed before the index date. We also excluded patients for whom we could not determine the sex or age. For each benzodiazepine case,we randomly selected one insured person from the non-benzodiazepine cohort who had no history of
benign brain tumors, malignant brain tumors, or benzodiazepine treatment. Moreover, each person selected was of the same sex, age (every
5 years), and index date year. The non-benzodiazepine cohort totaled 62,050 patients (mean age = 45.7 years, SD = 14.3 years).
2.3. Outcome measures
The person-years of follow-up were estimated for the study participants from the index date until the diagnosis of benign brain tumors
(BBTs) (ICD-9-CM code 225) or malignant brain tumors (MBTs) (ICD-9-CM codes 191, 192, 194.3 and 194.4) or censored because of death, loss to follow-up, withdrawal from the insurance system, or December 31, 2010.
The baseline comorbidities and treatment that may be associated with BBTs and MBTs were identifed before the end dates (the date of BBT or MBT diagnosis, date the patient was lost to follow-up, date of death, date of withdrawal from insurance, or fnal day of 2010) for the
participants in both cohorts. Comorbidities and treatments that were considered in the data analysis included stroke (ICD-9-CM code 430– 438), dementia (ICD-9-CM code 290.0–290.4, and 331.0), epilepsy (ICD-9-CM code 345), head injuries (ICD-9-CM 850–854, and 959.01), and brain CT/MRI examinations (ICD-9-OP procedure code 870.3 and 889.1).
For further analysis, we divided the benzodiazepine cohort into 4 groups, according to their disease status, as follows: (1) those with sleep disorders (ICD-9-CM codes 370.4 and 780.5 [except for sleep apnea syndrome: codes 780.51, 780.53, and 780.57]); (2) those with anxiety (ICD-9-CM codes 300.0, 300.2, 300.3, 308.3, and 309.81); (3) those with both sleep disorders and anxiety; and (4) those with neither.
2.4. Statistical analysis
Demographic factors, including age, sex, residential status, comorbidities and treatment, were compared between the benzodiazepine
cohort and non-benzodiazepine cohort by using the χ2 test. The incidence
densities of BBTs and MBTs in both cohorts were calculated.
Poisson regression models were used to evaluate the benzodiazepine cohort to non-benzodiazepine cohort incidence rate ratio (IRR) with 95% confdence intervals (CIs). Univariable and multivariable Cox proportional hazard regression analyses were performed to assess the risk of developing BBTs and MBTs associated with benzodiazepine use, compared with non-benzodiazepine cohort. The multivariate models
were simultaneously adjusted for demographic characteristics, comorbidities and brain CT, or MRI examinations. Hazard ratio (HR) and 95%
CIwere estimated in the Coxmodel.We further stratifed benzodiazepine according to annual dosage taken to estimate the risk of BBT and MBT development associated with benzodiazepine use. All of the analyses were performed using the SAS statistical package (version 9.1 for Windows; SAS Institute, Inc., Cary, NC, USA). A two-tailed p-value lower than 0.05 suggests statistical signifcance.
3. Results
3.1. Characteristics of the study participants
Table 1 lists the characteristics of all of the 124,236 study participants in both the benzodiazepine and non-benzodiazepine cohorts.
Approximately 31.9% of the patients were young, between 20 and 39 years of age. There were more women than men in both cohorts
(52.8% vs 47.2% and 52.1% vs 47.9%, respectively). In both cohorts, more patients were living in urban areas (59.8% and 61.6%, respectively). Compared to the non-benzodiazepine cohort, the benzodiazepine
patients were more likely to have a stroke (2.82% vs 8.28%), dementia (0.49% vs 2.05%), epilepsy (0.35% vs 2.05%), head injury (3.37% vs 8.06%), and brain CT or MRI examinations (2.38% and 7.59%). 3.2. Incidence rate ratios of BBTs and MBTs
The overall incidence of BBTswas 3.33-fold higher in the benzodiazepine cohort than in the non-benzodiazepine cohort (46.3 vs 13.9 per
100,000 person-years, IRR = 3.33, 95% CI = 3.17–3.50) (Table 2). The
overall incidence ofMBTswas also signifcantly higher in the benzodiazepine cohort than in the non-benzodiazepine cohort (3.71 vs 2.02 per
1000 person-years, IRR = 1.84, 95% CI = 1.75–1.93). The age-specifc analyses showed that BBTs were signifcantly highest for those
aged 50–59 years in the benzodiazepine cohort than the nonbenzodiazepine cohort (IRR = 4.30, 95% CI = 3.84–4.81). Agespecifc
benzodiazepine cohort-to-non-benzodiazepine cohort incidence densities of MBTs increased with age in both cohorts and
comparison of benzodiazepine cohort with non-benzodiazepine cohort showed that the IRR ofMBTs decreasedwith age (fromIRR = 3.82, 95% CI = 3.44–4.25 in the ≤39-year-old age group to IRR = 1.28, 95%
CI = 1.16–1.40 in the ≥60-year-old age group). 3.3. Hazard ratios of BBTs and MBTs After adjusting for age, sex, comorbidities and brain CT, or MRI
examinations, benzodiazepine cohort had a 3.15-fold increased risk of developing BBTs compared to the non-benzodiazepine cohort (adjusted HR = 3.15, 95% CI = 2.37–4.20). With an adjusted HR of 3.74 (95% CI = 2.02–6.92), the age-specifc relative risk of BBTs was highest for those aged 50–59 in the benzodiazepine cohort, as compared with the
non-benzodiazepine cohort. Table 3 shows that the benzodiazepine
cohort with anxiety had a 3.76-fold higher risk of BBTs (95%
CI = 2.52–5.25). Comparedwith non-BZD cohort, those in the benzodiazepine cohort with sleep disorders and anxiety had a 3.64-fold higher
risk of developing BBTs (95% CI = 2.36–4.62), followed by benzodiazepine cohort without sleep disorders and anxiety (adjusted HR = 3.30,
95% CI = 2.36–4.62) and benzodiazepine cohort with sleep disorders (adjusted HR = 2.23, 95% CI = 2.50–3.31). To examine the dose–response relationship between benzodiazepine use and BBTs/MBTs risk.
the adjusted HRs of BBTs increased with benzodiazepine dosage (adjusted HR = 2.12, 95% CI = 1.45–3.10, for 36–150 mg/year; adjusted
HR = 7.03, 95% CI = 5.19–9.51, for ≥ 151 mg/year). 4. Discussion
The results of the adjusted analysis fromthe population-based study indicated that benzodiazepine use signifcantly increases the risk of subsequently developing benign brain tumors. We could not fnd increases of the risk of developing malignant ones, which is probably
due to the small number of patients with malignant brain tumors in this study. Additionally, malignant brain tumors include metastatic as well as primary lesions,which could confound themechanistic relationship of the results. The most frequently reported benign brain tumor is meningioma (tumors of the meninges, 24.0% of brain tumors), and the most frequently reported malignant tumor is glioblastoma (tumor of the neuroepithelial tissues, 22.6%). This implies that, in most instances, benign and malignant brain tumors are derived from different histologies,
and thus have different genetic andmolecular expressions [13–15].
The risk of benign brain tumor diagnosiswas highestamong patients in their sixtieswho used benzodiazepines for an extended period during their middle-aged years. The risk of developing benign brain tumors also exhibited a dose-dependent trend; if the benzodiazepine dosage was more than 36 mg per year, then there was a higher rate of tumor occurrence in the patients with anxiety, regardless of having a sleep disorder. These relevant fndings should be shared with medical providers worldwide because they might affect the daily prescription of
sleeping pills or other forms of benzodiazepine use. A possible explanation of our results is that patients with psychiatric conditions or sleep
disorders had more opportunities to undergo imaging examinations, resulting in more brain tumor diagnoses in these groups. However, a previous population-based study did not fnd Taiwanese patients with
depression to have a higher risk of overall cancer development [16].
Table 3 shows that the patients taking benzodiazepine without an anxiety or sleep disorder still had a higher risk of developing benign brain tumors. Another explanation is that slow-growing benign brain tumors are usually accompanied by dizziness, seizures, sleep disorders, and psychiatric conditions, which are frequently treated with benzodiazepines and warrant the patients that benzodiazepine use may harbor
Benzodiazepines enhance γ-aminobutyric acid neurotransmission by interacting with the GABA receptor-coupled chloride channel. Apart from its role as an inhibitory neurotransmitter, γ-aminobutyric acid is also believed to regulate various stages of cell proliferation and differentiation in the brain and periphery, and may be involved in
the growth of benign tumors in various ways [19,20]. However, the
potential mechanisms of benzodiazepines 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
[21]. Richardson et al. found benzodiazepine-GABA(A) receptor
binding is very low in dysembryoplastic neuroepithelial tumor, a
benign brain tumor [22]. Recently, Bode et al. reported that knockdown
of the peripheral type benzodiazepine receptor (now known as translocator protein, TSPO) as well as exposure to TSPO ligands
enhances brain tumor proliferation in an animal model [23]. Those
implied that the expression of benzodiazepine binding affnity might also play a role in the neoplastic growth of the brain. The peripheral benzodiazepine receptors were reported as being present in most brain tumors. However, the lack of expressing its characteristics in a malignant brain tumor from the neuroepithelial tissues, anaplastic astrocytoma, might explain the lower risk of developing malignant
brain tumors than developing benign ones in our results [24–26].
One of the strengths of this study is its nationwide population-based design and representativeness. However, the study has some limitations. First, detailed information, such as smoking habits, alcohol
consumption, body mass index, socioeconomic status, and family history of cancer,were not available in the NHIRD, all ofwhich aremajor risk
factors for brain tumors and could plausibly be associatedwith benzodiazepine. However, because the NHIRD encompasses nearly all of
Taiwan's population, and because the reimbursement policy is universal, it is unlikely that these factors would affect the prescription of
benzodiazepine. Second, the evidence derived from a cohort study is generally lower than that from randomized control trials, because a cohort study design is subject to many biases related to confounding adjustment. Despite our meticulous study design with an adequate control of confounding factors, a key limitation is that bias
could still remain if there are unmeasured or unknown confounders. Third, the diagnoses in NHI claims primarily serve the purpose of administrative billing and do not undergo verifcation for scientifc purposes. We were not able to contact the patients directly about their benzodiazepine use because of the anonymity of their identifcation numbers. Moreover, prescriptions for these drugs before 1996
could not be used in our analysis. This could have resulted in an underestimated cumulative dosage and may have weakened the observed association. However, the data on the prescription of BZD and cancer diagnosis were highly reliable.
In conclusion, in this population-based retrospective cohort study, we found a signifcant increase in benign brain tumor risk. Additional large unbiased, population-based studies and randomized control trials, regarding the relationship between brain tumor development and the use of various benzodiazepines, are necessary to support our fndings before any conclusion can be drawn.
