Trend analysis of adverse drug reactions to sedative-hypnotics among residents in Jiangsu Province of China,2011

Abstract

Background

The safety of sedative-hypnotic drugs represents an underrecognized and crucial public health concern, despite their widespread use.

Objective

The objective of this study was to investigate the characteristics and trends of adverse drug reactions (ADRs) to sedative-hypnotics in China.

Method

Data were extracted from the spontaneous reporting system (SRS) for ADR surveillance in Jiangsu Province. Sedative-hypnotic drugs for ADRs were coded using the Anatomical Therapeutic Chemical classification system. We used the Chinese modification of the International Classification of Diseases, Tenth Revision, to group primary diseases, and the Medical Dictionary for Regulatory Activities to classify the manifestation of ADRs. We analysed the characteristics of ADR reports, including demographic and sedative-hypnotics information, ADR involvement of system organs and clinical manifestations, and cost of ADRs. Joinpoint regression was employed to estimate age-adjusted ADR rates stratified by sex from 2011 to 2019, and the percentage change annualized estimator was used to evaluate trends over time.

Results

A total of 899 reports of ADRs to sedative-hypnotics were found, with 440 (49.1%) males and 459 (50.9%) females. Regarding ADRs to sedative-hypnotics, neurological disorders (310 cases, 34.5%) were the most common. An estimated cost savings of RMB 6031.98–54,287.82 (USD 826.38–7437.43) could be realised if 10%–90% of the ADRs in this study were reduced. The age-adjusted ADRs reporting rates increased significantly from 0.06 to 0.18 per 100,000 population during 2011–2019, representing an annual increase of 14.5% (95% confidence interval 9.4–19.9%; p-value < 0.001). There was a gender difference, with an age-adjusted ADRs annual increase of 14.0% (95% confidence interval 6.6%–21.9%; p-value 0.002) for males and 14.8% (95% confidence interval 7.5%–22.6%; p-value 0.002) for females.

Conclusions

Reports of sedative-hypnotic ADRs were on the rise during the study period, and there was a gender difference. More rational policies and systems are needed to promote the safe use of sedative-hypnotic drugs.

Keywords

adverse drug reactions sedative-hypnotic drugs trend analysis spontaneous reporting medication safety

Introduction

Drugs are regarded as necessary and intimately associated with human life, where diseases and cures might be induced by them.¹ The World Health Organization defines an adverse drug reaction (ADR) as ‘a response to a drug that is noxious and unintended and occurs at doses normally used in man for the prophylaxis, diagnosis or therapy of disease, or for modification of physiological function’.² The frequency with which adverse drug reactions are reported is rising annually due to the increasing range of medications and increased drug use.³ People who live in fast-paced modern societies are more likely to suffer from depression, sleeplessness, and other psychological disorders.⁴ Given this, people often resort to medication, particularly sedative-hypnotic drugs, to alleviate the distress of these diseases.⁵

Sedative-hypnotic drugs that induce drowsiness and promote sleep, have a wide range of depressant effects on the central nervous system.⁶ The prevalence of insomnia has been rising and affecting younger populations, with as many as one-third of the world’s adult population suffering from insomnia.⁷ The consumption of sedative-hypnotics in countries has been on the rise in recent years due to insomnia exacerbated by the novel coronavirus infection (COVID-19) pandemic.^8,9 An increasing number of patients are becoming chronically dependent on and abusing sedative-hypnotic drugs, which can cause multiple health risks, including falls,¹⁰ depression and anxiety, cognitive impairment,^11,12 and risk of death.¹³ This could significantly expose individuals to mental and physical diseases as well as place a heavy burden on families and society. Consequently, there is a great need for healthcare professionals, patients, and regulatory systems to pay attention to changing trends in ADRs reporting for sedative-hypnotic drugs.

Unfortunately, to the best of our knowledge, few studies have explored the health effects of ADRs for sedative-hypnotic drugs on Chinese residents. Most of previous relevant studies only involved developed countries such as the United Kingdom and the United States,^14,15 not mainland China. Therefore, using province-wide data retrieved from the ADRs spontaneous monitoring system, this study aimed to investigate the trend of ADRs reporting rates of sedative-hypnotic drugs among residents of Jiangsu Province, China, from 2011 to 2019 to provide a theoretical reference for optimising the rational administration of these drugs.

Methods

Data source and screening

We extracted data for 2011–2019 from the spontaneous reporting system (SRS) for ADR surveillance in Jiangsu Province. The sedative-hypnotics were defined as prescription anxiolytics and hypnotics and sedatives using the Anatomical Therapeutic Chemical (ATC) Classification System recommended by the World Health Organization. Notably, although this classification system lists clonazepam as an antiepileptic, it belongs to the sedative-hypnotics of benzodiazepines according to National Medical Products Administration (NMPA) standards in China.¹⁶ Given that this study focused on the ADRs of sedative-hypnotics within the Chinese pharmacovigilance system, we categorized clonazepam as a sedative-hypnotic drug. With a population catchment of about 84.7 million people for ADRs monitoring, the Jiangsu ADR Surveillance System was founded in 2001. Three levels of ADRs monitoring agencies – one top-tier provincial agency, thirteen secondary-tier municipal agencies, and ninety-five primary-tier county agencies – constitute Jiangsu Province’s pharmacovigilance system. These agencies are responsible for gathering, assessing, and compiling ADRs cases. The ADRs database contains details on suspected medicines, the age and gender of the anonymized patients, and an evaluation of the causality of ADRs. The pharmacovigilance database is subject to quality control measures that have been put in place by various levels of ADRs monitoring agencies. These measures include routinely reviewing and verifying ADRs reports, cross-checking data for accuracy and completeness, and conducting on-site investigations of fatal cases. When the ADRs cases were added to the database, clinical pharmacists and other medical professionals with extensive clinical and pharmaceutical knowledge assessed the causal relationships between the suspected medications and the reported adverse events. In order to assess the temporal relationship, consistency, intensity, and specificity of ADRs, the evaluation standards were adapted from the World Health Organization Uppsala Monitoring Centre (WHO-UMC) system¹⁷ and the Administrative Measures for the Reporting and Monitoring of Adverse Drug Reactions¹⁸ issued by the Ministry of Health of China.

Based on an ethical review and data use agreement with the Jiangsu Center for Adverse Drug Reaction Monitoring [JSADRs#2021/0101], this study extracted residents’ age, gender, ADRs severity, primary disease, suspected medication, ADRs onset time and outcome, and other information from data records with de-identified information. We categorized the severity of ADRs into four types based on China’s Administrative Measures for the Reporting and Monitoring of Adverse Drug Reactions,¹⁸ that is, serious, new serious, non-serious, and new non-serious. Among them, serious ADRs were adverse drug reactions that could result in any of the following conditions: death, life-threatening, hospitalisation or prolonged hospitalisation, permanent or significant disability/incapacity, or other significant medical condition. The outcome of ADRs was categorized as recovered, improved, not improved, and unknown. After excluding reports with missing manufacturer details (n = 168), missing age (n = 18), missing gender (n = 3), duplicate reports (n = 36), and missing routes of administration (n = 12), the final screening of reports assessed as ‘certain’ (n = 104), ‘probable’ (n = 484), and ‘possible’ (n = 311) resulted in the inclusion of 899 reports in our study. ADRs involvement of systems and organs and classification of adverse reaction names were based on the Medical Dictionary for Regulatory Activities (MedDRA).¹⁹ After the types of ADR reports were categorized as serious, new serious, non-serious, and new non-serious, we analysed their treatment costs (the average treatment cost per case) and cost savings (the savings from 10% reduction in ADRs and the savings from 90% reduction in ADRs).

Statistical analysis

Numbers and proportions of data were calculated in this study to describe characteristics such as different age groups, gender, ADRs involvement in organ systems, ADRs severity, ADRs onset time and ADRs outcome. We standardised the annual crude rate of ADRs reporting taking the total number of actual cases annually as the numerator (based on the number of ADRs reports in Jiangsu Province for the period 2011–2019) divided by the population at the end of that calendar year as the denominator.²⁰ Considering that the age structure of the population may change over time, the national census population counted by the National Bureau of Statistics (NBS) in 2010 was used as the standard population for direct age standardisation, with further calculations of age-standardised rates by gender.²¹ The Joinpoint regression, combined with annual percentage change (APC) and 95% confidence intervals (CI) was performed to evaluate the trend of adverse reaction reporting rates for sedative-hypnotic drugs over time. The age-standardised rates of ADRs in 2011 and 2019, along with the Annual Percent Change (APC), Average Annual Percent Change (AAPC) and 95% CI for the period from 2011 to 2019, were reported in the present study. All p-values less than 0.05 were considered statistically significant. Data analysis was performed using SPSS Version 25, Joinpoint Version 4.9.1.0 software.

Results

Characteristics of the study population

From 2011–2019, a total of 899 cases of adverse reactions to sedative-hypnotic drugs in Jiangsu Province were analysed in this study, including 440 (49.1%) male and 459 (50.9%) female cases. We categorised the study population into 0–14, 15–59 and over 60 years of age, with the highest number of ADRs cases in the 15–59 age group (452; 50.3%), followed by over 60 years (385; 42.8%), and lastly 0–14 years (62; 6.9%). We found 52 (5.8%) cases of serious ADRs, majority of ADRs with favourable outcome. Regarding the outcome of ADRs, 290 (32.3%) recovered, 548 (61.0%) improved, 39 (4.3%) did not improve, and the outcome of 22 (2.4%) was unknown. Of all ADRs reported for sedative-hypnotic medications, 53.5% occurred ≤1 day (24 h) after treatment, 21.5% occurred in 2–7 days, and 24.7% occurred >1 week later. The median time to occurrence of sedative-hypnotic ADRs in our study was ≤24 hours, with an interquartile range of 6 days. Oral administration was the most predominant mode of administration, accounting for 72.0% of all ADRs reported, while injectable administration and other routes of administration were relatively less common.

Sedative-hypnotics involved in ADRs reports

We found that the main sedative-hypnotic drugs involved in ADRs reports in Jiangsu Province were clonazepam (220; 24.5%), zopiclone (180; 20.0%), eszopiclone (146; 16.2%), and dexmedetomidine hydrochloride injection (118; 13.1%), which together accounted for 73.8% of all reports. Relevant information is presented in Table 1.

Table 1.

Sedative-hypnotic drugs primarily involved in ADRs reports.

Drugs	Numbers	Proportions (%)
Clonazepam	220	24.5
Zopiclone	180	20.0
Eszopiclone	146	16.2
Dexmedetomidine hydrochloride injection	118	13.1

ADRs: adverse drug reactions.

ADRs involvement of system organs and clinical manifestations

In the 2011–2019 ADRs reports of sedative-hypnotic drugs in Jiangsu Province, the top five systems and organs involved were nervous system disorders (310; 34.5%), gastrointestinal disorders (142; 15.8%), general disorders and administration site conditions (96; 10.7%), skin and subcutaneous tissue disorders (82; 9.1%), and vascular disorders (69; 7.7%). The corresponding clinical manifestations are shown in Table 2.

Table 2.

System organ involvement and clinical manifestations of the top five ADRs in this study.

System organs involved in the first five	Clinical manifestation	Numbers	Proportions (%)
Nervous system disorders	Drowsiness, dizziness, bitter mouth, extrapyramidal disorders, excessive sedation, mental disorders, etc.	310	34.5
Gastrointestinal disorders	Nausea, vomiting, dry mouth, constipation, diarrhoea, etc.	142	15.8
General disorders and administration site conditions	Fatigue, pain at injection site, oedema, chills, general weakness etc.	96	10.7
Skin and subcutaneous tissue disorders	Rash, drug rash, itching, maculopapular rash, exfoliative dermatitis, etc.	82	9.1
Vascular disorders	Hypotension, phlebitis, shock, hypertension, etc.	69	7.7

ADRs: adverse drug reactions.

Cost of ADRs

ADRs cause an increase in treatment costs, which are estimated to be RMB 552.25 (USD 75.66) on average per serious ADRs report, RMB 31.59 (USD 4.33) for a new serious ADRs report, RMB 38.70 (USD 5.30) for a non-serious ADRs report, and RMB 23.98 (USD 3.29) for a new non-serious ADRs report.^22–25 An estimated cost savings of RMB 6031.98–54,287.82 (USD 826.38–7437.43) could be realised if 10%–90% of the ADRs in this study were reduced. The details are provided in Table 3.

Table 3.

Average cost of treatment and savings for different types of ADRs.

Types of ADRs reports	Numbers	Average treatment cost per case (RMB/USD)	Savings from 10% reduction in ADRs (RMB/USD)	Savings from 90% reduction in ADRs (RMB/USD)
Serious	52	552.25/75.66	2871.70/393.42	25845.30/3540.81
New serious	6	31.59/4.33	18.95/2.60	170.59/23.37
Non-serious	764	38.70/5.30	2956.68/405.07	26610.12/3645.59
New non-serious	77	23.98/3.29	184.65/25.30	1661.81/227.67
Total	899	646.52/88.57	6031.98/826.38	54287.82/7437.43

ADRs: adverse drug reactions; RMB: Renminbi; USD: United States Dollar.

Trend analysis of ADRs for sedative-hypnotics

Total population analysis

Figure 1 illustrates the overall increasing trend of the standardised reporting rate of sedative-hypnotic ADRs in Jiangsu Province. The overall standardised rate increased from 0.06/100,000 in 2011 to 0.18/100,000 in 2019, with an APC = AAPC = 14.5% (95% CI: 9.4%–19.9%, p < 0.001). This showed that the reported rate of sedative-hypnotic ADRs in Jiangsu Province increased annually by an annualized rate of 14.5% overall.

Figure 1.

The trend in age-standardised rates of ADRs for the overall sedative-hypnotics.

Gender stratification analysis

Figures 2 and 3 display the trends in ADR reporting rates for sedative-hypnotic ADRs over time for males and females, respectively. Although they both exhibited a steady upward trend, gender differences still existed. The standardised rate among males increased from 0.06/100,000 in 2011 to 0.17/100,000 in 2019, with an APC = AAPC = 14.0% (95% CI: 6.6%–21.9%, p = 0.002). It showed an average annual increase of 14.0% in the reported rate of sedative-hypnotic ADRs in males in Jiangsu Province from 2011 to 2019 (Figure 2). The standardised rate among females increased from 0.06/100,000 in 2011 to 0.19/100,000 in 2019, with an APC = AAPC = 14.8% (95% CI: 7.5%–22.6%, p = 0.002). This suggested an average annual increase of 14.8% in the reported rate of sedative-hypnotic ADRs in females in Jiangsu Province from 2011 to 2019 (Figure 3).

Figure 2.

The trend in age-standardised rates of ADRs for sedative-hypnotics (males).

Figure 3.

The trend in age-standardised rates of ADRs for sedative-hypnotics (females).

Discussion

Summary of the main findings

This study included 899 reports of sedative-hypnotic ADRs, with slightly more female patients than males. We found that most of the patients were clustered in the age group of 15–59 years, a possible explanation is that this group suffers from greater insomnia distress due to academic or work pressures in their lives,^26,27 where they tend to use sedative-hypnotic drugs as a way of coping,²⁸ which makes them prone to developing ADRs. Notably, older adults are more susceptible to ADRs due to pharmacokinetic changes and polypharmacy.²⁹ However, several factors may explain their underrepresentation in our cohort. First, the population base over 60 years old is smaller compared to the 15–59 age group in our study. Second, ADRs in the elderly might be underreported, as adverse events can be misattributed to comorbidities or normal ageing.³⁰ Third, clinicians may prescribe sedative-hypnotics more cautiously in older adults due to established guidelines on increased risks,³¹ potentially reducing exposure. The relatively low ADR incidence observed in the 0–14 age group should not obscure pharmacological risks in children. Given their developing organ systems, immature immunity, and reduced metabolic competence,³² this population requires particular vigilance regarding adverse drug reactions.

We found that oral administration was the most common route of administration for sedative-hypnotic drugs, probably because of its convenience, safety, and acceptability.³³ Adverse reactions to sedative-hypnotic drugs were mainly focused on the nervous system, which may be related to their specific pharmacological mechanisms.³⁴ One plausible explanation for clonazepam being the sedative-hypnotic drug most predominantly involved in ADR reports is that it is a long-acting benzodiazepine with a long half-life.³⁵ Most patients would take the oral route to use sedative-hypnotic drugs to rapidly induce and prolong sleep, or to manage other symptoms such as anxiety and epilepsy.³⁶ However, growing research is focusing on the concerns associated with the ingestion of sedative-hypnotic drugs, such as drug safety, dependence, and abuse.³⁷ As psychoactive substances, these drugs inhibit the cells of the central nervous system through their own pharmacological action, which may result in neurological disorders such as drowsiness, mental incapacity, and slowness of thought.³⁸ The sedative-hypnotic drug with the highest number of reported cases in our study was clonazepam, which is consistent with surveys in other parts of China.³⁹ Although clonazepam is classified as an antiepileptic by the ATC, it belongs to the sedative-hypnotics of benzodiazepines based on NMPA standards in China.¹⁶ Another study revealed that benzodiazepines are currently the dominant sedative-hypnotics in clinical practice, and also frequently reported as drugs used for non-medical purposes and abuse.⁴⁰

The issue of patient losses due to ADRs has been of public concern, both in terms of the direct financial burden of health treatment and the potential financial losses associated with time off or missed work.⁴¹ It was observed in Table 3 that the proportion of serious and new serious types of reports was significantly lower than the average, but the direct costs they incurred were the majority. ADRs may place a financial burden on patients and affect their quality of life. An estimated cost savings of RMB 6031.98–54,287.82 (USD 826.38–7437.43) could be realised if 10%–90% of the ADRs in this study were reduced. It is essential that effective interventions should be taken to reduce the occurrence of ADRs, so that economic losses could be reduced for society and families. When patients follow the doctor’s instructions and physicians choose to use drugs in a reasonable way to treat diseases, the incidence of ADRs would be lessened to a certain extent, which brings the intuitive effect that the treatment cost can be decreased, and the time and energy cost paid by patients due to diseases could also be reduced.⁴² Meanwhile, strengthening the quality control of pharmaceutical manufacturers and improving the products according to the characteristics of ADRs can also effectively prevent the occurrence of ADRs.⁴³

In this research, age-adjusted standardised rates of ADRs for sedative-hypnotics were increasing annually in both overall population analyses and sex-stratified analyses, with lower annualised growth rates in males than in females. A study has reported that the annual rate of reported ADRs in children aged 0–14 years was increasing, suggesting that there is a need to enhance the safety of the paediatric medication environment and to pay attention to the physiological discomforts associated with the absorption, distribution, metabolism and elimination of medications in children.³² Another report pointed out that the proportion of people over 65 years of age reporting ADRs in China continued growing in 2009–2020, indicating that the aggravation of population ageing might be the main reason for the increase in the number of reports from the elderly.⁴⁴ Furthermore, the actual amount of sedative-hypnotic ADRs would be greater than presently observed, possibly due to symptoms such as anxiety and tremor resulting from discontinuation of these medications not being taken seriously by physicians.⁴⁵ Similar to our study, a 2012–2018 study showed significantly higher intake of sedative-hypnotic drugs and ADRs in adolescent populations in Sweden, Norway, and Denmark.⁴⁶ The annually increasing ADRs rates for sedative-hypnotic drugs were more pronounced in females, which might be due to physiological or hormonal differences,^47,48 with the specific mechanisms behind these differences to be investigated in further studies.

Perspectives and significance

There is no doubt that sedative-hypnotic drugs are effective in treating insomnia and reducing stress, but little is known about the evidence of ADRs associated with such medications in China. This study analysed ADRs data for sedative-hypnotic drugs in residents of Jiangsu Province, China, from 2011–2019. The results showed that neurologic dysfunction was the most common among the adverse effects of sedative-hypnotic drugs. Moreover, there was an increasing trend in the reporting rates of sedative-hypnotic ADRs over the study period, with females appearing to be more sensitive than males. Our findings indicate that the safety of sedative-hypnotic drugs poses an essential health concern, and sustained studies in this area are required to fill relevant knowledge gaps. Meanwhile, we recommend that government departments could develop more rational policies and systems to promote the safe use of sedative-hypnotic drugs.

Strengths and limitations

The strengths of this research included the retrospective analysis using reported data on sedative-hypnotic ADRs in the province of Jiangsu from 2011–2019, an updated trend analysis employing Joinpoint software, and informative recommendations for policymakers and medication safety advocates to consider appropriate countermeasures to reduce the risk of sedative-hypnotic ADRs. Nonetheless, there were limitations to this paper. First, information on some of the drugs we investigated was uncertain, and the terminology applied in the agencies’ reports was not consistent, which might contribute to some bias or misclassification. Second, there were some ADRs reports with missing individual items that were excluded, which may also result in variations in reporting rates. Third, detailed individual exposure characteristics, such as height, weight, and past medical history, were not available, making the assessment of the results obtained not as comprehensive as it could have been. Lastly, since China’s pharmacovigilance system remains at a developmental stage, there are inevitably some problems of variable quality of reporting, high rates of underreporting or zero reporting. Nevertheless, our findings were somewhat robust owing to the adoption of an established causality scheme based on an expert review of the best available surveillance data on adverse reactions to sedative-hypnotic drugs. Future research is expected to evaluate the risk-benefit ratio of sedative-hypnotics for better safety along with an investigation for potential risk factors associated with sedative-hypnotic ADRs.

Conclusions

This study demonstrated that ADRs of sedative-hypnotic drugs were a major health concern, showing an upward trend in reporting rates during 2011–2019 in Jiangsu Province, with severe economic burdens on both society and families. Moreover, this impact was more pronounced in females. Further investigations are required to elucidate the exact mechanisms behind these associations through extensive research in different regions. We appeal for more initiatives to decrease ADRs for sedative-hypnotics, emphasising that relevant authorities should develop collaborative working patterns and improve updated monitoring systems to facilitate the safety of sedative-hypnotics administration.

Supplemental Material

Supplemental Material - Trend analysis of adverse drug reactions to sedative-hypnotics among residents in Jiangsu Province of China, 2011–2019

Supplemental Material for Trend analysis of adverse drug reactions to sedative-hypnotics among residents in Jiangsu Province of China, 2011–2019 by in Jinxia Yu, Ming Li, Hui Xue, Yitao Liu, Lijun Fan, Jianjun Zou and Wei Du International Journal of Risk & Safety in Medicine

Footnotes

Acknowledgements

We would like to acknowledge the Jiangsu Center for ADR Monitoring for providing us with these data from our study.

ORCID iD

Jinxia Yu

Ethical approval

This study was approved in accordance with the ethical review and data use agreement with Jiangsu Center for ADR Monitoring (JSADRs #2021/0101).

Author contributions

W.D., J.Z., and J.Y. designed and conceptualised the manuscript; J.Y., M.L., Y.L., H.X., and W.D. collected, analysed, and interpreted the findings; J.Y., M.L., and Y.L. wrote the manuscript; W.D., L.F., and J.Y. received financial support; all authors reviewed the manuscript.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was supported by National Social Science Foundation of China (Grant no. 23CGL072), Ministry of Science and Technology (Grant no. G2023141005L), Ministry of Education (Grant no. 1125000172), SEU Innovation Capability Enhancement Plan for Doctoral Students (CXJH_SEU 24210), National Natural Science Foundation of China (Grant no. 82173899), and Jiangsu Provincial Department of Science and Technology.

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Data availability statement

The datasets generated from this study are not available to the public. On reasonable request, the corresponding author might make the aggregated data available.*

Supplemental Material

Supplemental material for this article is available online.

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Supplementary Material

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Trend analysis of adverse drug reactions to sedative-hypnotics among residents in Jiangsu Province of China,2011–2019

Abstract

Background

Objective

Method

Results

Conclusions

Keywords

Introduction

Methods

Data source and screening

Statistical analysis

Results

Characteristics of the study population

Sedative-hypnotics involved in ADRs reports

ADRs involvement of system organs and clinical manifestations

Cost of ADRs

Trend analysis of ADRs for sedative-hypnotics

Total population analysis

Gender stratification analysis

Discussion

Summary of the main findings

Perspectives and significance

Strengths and limitations

Conclusions

Supplemental Material

Supplemental Material - Trend analysis of adverse drug reactions to sedative-hypnotics among residents in Jiangsu Province of China, 2011–2019

Footnotes

Acknowledgements

ORCID iD

Ethical approval

Author contributions

Funding

Declaration of conflicting interests

Data availability statement

Supplemental Material

References

Supplementary Material