Introduction
Over half a million people annually suffer from irreversible hearing loss (HL) as a result of receiving therapeutic medications with ototoxic side effects [1]. Drug-induced ototoxicity is described as a functional impairment characterized by transient or permanent inner hair cell damage caused by therapeutic medications [2]. It can include hearing and/or balance abnormalities, depending on the involvement of the cochlear and/or vestibular system, respectively, or both. The majority of ototoxicity events resolve on their own when therapy is stopped, but a few frequently have major long-term effects that lower the patient’s quality of life [3].
In contemporary medicine, ototoxicity is a major problem [4]. Proton pump inhibitors (PPIs), analgesics, antibiotics, anticancer treatments, and antihistamines are only a few of the pharmaceuticals that have been linked to ototoxicity. Due to the widespread usage of these medications for a variety of therapeutic goals among diverse patient populations, research on their possible negative effects on hearing and balance is crucial [5].
There is ample evidence of ototoxic effects associated with medications including antibiotics (like aminoglycosides), anticancer medicines (like cisplatin), and some painkillers [6]. These medications cause ototoxicity by a variety of methods, such as direct harm to the cochlear hair cells, interruption of the inner ear’s blood supply, or cellular metabolic disturbance. Even though these medications have clinical value, it is important to carefully weigh the risks and benefits of using them, particularly in groups where HL is already a concern, due to the possibility that they could permanently harm hearing [7,8].
A recent survey [9] revealed that a third of Americans over 50 reported that HL significantly affects their mental wellbeing. A majority (55%) report a discernible negative influence on their capacity to derive enjoyment from entertainment. Substantial percentages also highlight adverse effects on other domains, including 42% experiencing a detrimental impact on their social interactions, 40% on personal relationships, 32% on mental health, and 31% on the ability to carry out routine day-to-day activities.
There are over 600 medicines that may be ototoxic, according to multiple publications. However, there is a chance that certain medications’ ototoxic effects go unnoticed. Therefore, it is important for clinical sectors to investigate the potential for drug-induced ototoxicity [10,11].
Clinical approaches to reduce ototoxicity include determining which patients are at risk, keeping an eye on medication concentrations, conducting follow-up hearing evaluations, and transferring to less ototoxic treatment [12]. The aging population in Korea is more prone to HL due to the widespread use of these medications, which emphasizes the need to regularly monitor and assess the ototoxic effects of commonly used drugs. Understanding the connection between these drugs and ototoxicity is crucial for both preventive and therapeutic methods, as HL can seriously lower quality of life, particularly in the elderly [8].
By analyzing national health data from Korea and performing research on ototoxic medications and their effects on hearing, this study attempted to meet these demands. By using this two-pronged strategy, the research hopes to give medical professionals useful knowledge about the ototoxic hazards connected to regularly prescribed medications in Korea, which will ultimately lead to safer prescription practices and improved patient outcomes.
Subjects and Methods
National health data analysis
The Health Insurance Review & Assessment Service (HIRA) contributed sample data for this study, which was based on hospital visit records of National Health Insurance (NHI) subscribers from 2009 to 2016. The International Classification of Diseases-10 (ICD-10) codes were used to identify individuals with HL diagnoses, and the data was then utilized to compare the patients with a control group that did not have HL. This study was approved by the Institutional Review Board of Yonsei University Wonju Severance Christian Hospital (Wonju, South Korea) (CR321316). We obtained data access permission from HIRA, and the period during which we could use the data was from August 4, 2022, to December 31, 2022. The approval numbers for this study obtained from HIRA are M20210430249 and M20221005002.
All NHI registrants with at least one hospital visit record during the study period were included in the study population. It was looked at how the control group and patients with HL were distributed. Approximately 0.8% of all patients were found to have HL; in the latter two years of the research, this percentage increased slightly to 0.9% and 1.0%.
Study design and statistical methods
The primary objective of this study is to evaluate the impact of ototoxic medications on the incidence of HL.
Operational definition of hearing loss
Hearing loss was defined based on ICD-10 criteria. Patients were considered to have HL if they had a primary diagnosis code corresponding to sensorineural HL or other types of HL, and had at least one outpatient or inpatient record indicating such a diagnosis. The ICD-10 codes for sensorineural HL are listed in Table 1. Additionally, medical histories such as hypertension, diabetes, other vascular diseases, and chronic kidney disease were also taken into account.
Classification of medications
Medications were classified by identifying the common active ingredients of the most frequently used PPIs, analgesics, antibiotics, antineoplastic agents, and antihistamines worldwide through a systematic literature review (Table 2). If a patient took a specific active ingredient at least once during a given year, they were considered to have used that medication.
Statistical analysis
All statistical analyses were performed using SAS version 9.4 (SAS Institute Inc.). Descriptive statistics was done to summarize the characteristics of the study population and the prevalence of HL. And subgroup analyses were done to explore differences between HL and control groups in gender, age, medical history, and medication usage. Analysis of the annual distribution of ototoxic medication components wad done.
Results
According to the data from 2009 to 2016, the HL group increased slightly from 0.8% to 1.0% of the total sample, while the control group decreased slightly from 99.2% to 99.0% during the same period (Table 3). In terms of gender distribution, the proportion of males in the HL group ranged from 45.6% to 47.6%, whereas the proportion of males in the control group remained steady between 48.4% and 48.8%. Regarding age distribution, the proportion of individuals aged 65 and over in the HL group increased from 34.1% to 41.4%, while the proportion in the control group increased slightly from 10.6% to 13.3%. A significant majority of the control group remained under 65 years of age.
The prevalence of specific diseases was consistently higher in the HL group compared to the control group. For example, hypertension was reported at 24.7% to 25.7% in the HL group, compared to 11.4% to 12.6% in the control group. Diabetes prevalence in the HL group ranged from 10.6% to 12.3%, while in the control group it ranged from 4.4% to 5.9%. Other vascular diseases and chronic kidney disease also had higher rates in the HL group. In terms of medication use, 96.0% to 98.5% of the HL group used medication, whereas 91.8% to 92.7% of the control group used medication. Overall, the data indicates that individuals with HL are generally older and have a higher prevalence of various health conditions. Additionally, medication use is more common among those with HL, though the difference is relatively small.
Most PPI components showed an overall increase in usage and proportion, although distinct patterns were observed for different components. Esomeprazole magnesium trihydrate and rabeprazole sodium exhibited significant increases, with rabeprazole sodium, in particular, showing a sharp rise in usage proportion from 2013, reaching 1.17% in 2016, the highest among PPIs. Conversely, pantoprazole sodium sesquihydrate and revaprazan initially had high usage but later declined, nearly reaching 0% by 2016.
Painkillers such as acetaminophen, loxoprofen sodium, and ibuprofen generally maintained high usage. Acetaminophen sustained a high usage proportion of 10%–12%, despite some annual fluctuations. Tramadol hydrochloride experienced a significant drop in usage after 2014 compared to 2013, though it still maintained substantial usage. Etoricoxib and sufentanil citrate had minimal to no usage across most years, while naloxone hydrochloride was first reported in 2016.
Among antibiotics, the cephalosporin cefaclor maintained the highest usage, with proportions ranging from 4.07% to 4.50%. The penicillin antibiotic amoxicillin steadily increased in usage until 2012, then sharply declined to 0.17% in 2013, but later rebounded to 2.24%.
Anticancer agents showed relatively low usage compared to other drug categories, likely due to their application in a specific patient group, namely cancer patients. Among them, cisplatin and doxorubicin hydrochloride had higher usage, with doxorubicin hydrochloride showing a recent increase. On the other hand, carboplatin maintained a relatively low usage.
The antihistamine chlorpheniramine maleate consistently recorded very high usage across all years, with a continual increase observed. Bepotastine salicylate showed a gradual rise in usage after 2013, while levocetirizine HCl and cetirizine HCl maintained stable usage, indicating their continued effectiveness as allergy treatments.
The decrease in the usage proportion of certain drugs may be linked to the discovery of new side effects or increased awareness of the risks associated with long-term use, as well as the rise in alternative treatments. Conversely, a sustained or increasing usage proportion suggests a strong trust in the drug’s efficacy and safety. Furthermore, the emergence of drug usage in specific years indicates its introduction as a new therapeutic option.
Discussion
This study aimed to address these needs by conducting a study on ototoxic drugs and their effects on hearing, alongside an analysis of Korean national health data.
The examination of data spanning from 2009 to 2016 offers significant understandings into the epidemiology of HL and medication use in the Korean populace. The aging population and the rising prevalence of comorbidities, including diabetes, hypertension, and chronic renal disease, may be to blame for the HL group’s 1.0% prevalence increase from 0.8%. This raises concerns about public health. These results are consistent with previous research showing that aging and the existence of long-term medical problems are important risk factors for HL [13,14].
Age-related hearing loss (ARHL) was shown to be the most common type of HL, involving 65% of persons over the age of 60. Of these, 25% had moderate or worse HL (≥35 dB HL [decibels hearing level] in the better hearing ear). In the early stages, it is characterized by a symmetrical and bilateral loss of high frequency hearing (≥8 kHz). As the condition progresses, damage to the auditory nerves, which are essential for hearing, and the irreversible loss of cochlear hair cells impair hearing at lower frequencies [15]. Aging, health comorbidities, lifestyle, environment, and genetic factors all play a role in the development of ARHL [16,17]. Reactive oxygen species are produced by inflammation-related processes that are aided by these variables [18].
Regarding the link between HL and chronic illnesses, Stevens, et al. [19] discovered that the prevalence of HL was less than 10% for those over 50, 20% for those over 60, over 40% for those over 70, and over 50% for those over 80 years old based on a meta-analysis of 42 studies from various regions worldwide. HL is frequently seen in conjunction with additional (chronic) illnesses [20,21]. Furthermore, stressful conditions brought on by chronic illnesses can intensify the body’s pro-inflammatory and pro-oxidant processes. Due to their interdependence, these processes can be found together in a variety of chronic illnesses, including ARHL [22]. In order to potentially reduce the risk of HL, it is crucial to monitor and manage these medical issues because the HL group is often older and has higher rates of comorbidities [23].
The research also showed that a number of drugs are often used by the general public, including pain relievers like acet-aminophen and PPIs like rabeprazole sodium and esomeprazole magnesium trihydrate. This finding is consistent with other research, such as a comprehensive assessment of 65 papers involving 28 million PPI users across 23 countries, which revealed PPIs to be among the most commonly used acid-suppressing medications worldwide [24]. Regarding drug-induced ototoxicity, earlier research found a link between PPI and HL [25,26].
Rabeprazole sodium usage increased significantly between 2013 and 2016, which may indicate a change in prescribing practices because of the medication’s perceived safety and efficacy [27]. But the possible connection between ototoxicity and these widely used drugs raises questions that need to be looked into further [28]. The extensive usage of these medications and the marginal rise in the prevalence of HL may point to the need for more cautious prescribing procedures and patient education about the dangers of long-term pharmaceutical use.
The population’s high acetaminophen, loxoprofen sodium, and ibuprofen consumption is consistent with earlier research [29,30]. On the other hand, ototoxic effects have been linked to the use of salicylates, such as aspirin, or large doses of nonsteroidal anti-inflammatory drugs. A number of processes, such as decreased vascular supply to the cochlea, inhibition of cyclooxygenase, and impairment of outer hair cell activity, may be involved in ototoxicity [31]. Theoretically, acetaminophen-induced depletion of cochlear glutathione could make the cochlea more vulnerable to noise-induced injury [32,33].
As for cephalosporin, cefaclor remained the the antibiotics most frequently used. Given that nausea, vomiting, loss of appetite, and abdominal pain are the most frequent side effects of cephalosporins, this could be explained by their low toxicity and overall safety [34].
The use of fluoroquinolones was reduced by 50%, according to the current study. Although randomized clinical trials revealed that fluoroquinolones were initially well tolerated, epidemiological studies that followed indicated a higher likelihood of serious, persistent, incapacitating, and permanent side effects [35].
The reported decrease in aminoglycoside use in the current study may also be related to its safety concerns, such as ototoxicity. Up to 57% of children receiving aminoglycoside treatment had HL, according to a prior review by Diepstraten, et al. [36]. Vestibulotoxicity or cochleotoxicity are two possible symptoms of inner ear toxicity. Tinnitus, sensorineural HL, and deafness can result from cochleotoxicity. Vestibulotoxicity manifests as ataxia, nystagmus, nausea, and vertigo. Amikacin, neomycin, and kanamycin are selectively cochleotoxic, whereas streptomycin and gentamicin are primarily vestibu-lotoxic. Tobramicin has the same effects on the vestibule and the cochlea [37,38]. However, the reported decrease in the use of some drugs, such antibiotics and pantoprazole sodium sesquihydrate, may indicate a greater awareness of the potential side effects of these drugs or the availability of substitute treatments [39]. This pattern may be a reflection of how the medical community has responded to new information about the dangers of these medications, such as the possibility of ototoxicity [40]. The emergence of newer, safer therapeutic choices that healthcare providers choose for their patients may also be linked to the decrease in usage [41].
Limitations
The limitations of this study should be considered when interpreting the results. The reliance on national health insurance data may not capture all cases of HL or medication usage, particularly in populations that do not frequently seek medical care. Additionally, the study’s observational nature makes it challenging to establish causality between drug use and HL. The HIRA sample data is randomly extracted annually, limiting the ability to track continuous medical histories of patients. The lack of access to past medical history necessitated the use of medical records within each specific year as a substitute. The potential for confounding factors, such as other medications or environmental exposures, may also affect the results. Moreover, the lack of detailed information on dosage and duration of medication use limits our ability to fully assess the risks associated with specific drugs.
Conlusions
This study highlights the need for further research into the relationship between commonly prescribed medications and the risk of HL. While the findings suggest that certain drugs may contribute to an increased risk of HL, more robust studies are needed to confirm these associations and to explore the underlying mechanisms. Healthcare providers should be cautious when prescribing medications known to have ototoxic potential, especially to vulnerable populations such as the elderly or those with pre-existing health conditions. Future research should also focus on developing guidelines for safer drug use to prevent HL and improve patient outcomes.
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