STRENGTHS AND LIMITATIONS OF THIS STUDY
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This study uses a national sample from a nationwide claims database of individuals with private insurance with the time frame of this study spanning 12 years.
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This study uses a very specific population (all individuals who have already received sedatives) which minimises the selection bias to a certain extent.
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This is an association study comparing associations between coprescribing and comorbidities, including mental health comorbidities, and does not include all the conditions that could be associated with coprescribing.
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There were a lot of missing data for pharmacies that filled both sedatives and opioids for a patient.
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The study time includes 1 year after the initial release of the Food and Drug Administration and Centers for Disease Control and Prevention’s guidance on sedative and opioid prescribing which may not be adequate to observe the true impact of these recommendations on prescribing trends over time.
Introduction
Sedative hypnotics such as benzodiazepines, barbiturates and z-drugs (zolpidem, zaleplon and eszopiclone) are commonly prescribed for the treatment of seizures, anxiety and insomnia.1–3 While sedative medications may be clinically indicated in these disease states, their use is not without risk. Sedative hypnotics depress the central nervous system (CNS) and can cause significant respiratory depression, which if left unattended can lead to cardiac arrest and subsequent death.4 This risk is greatly heightened when taken with other medications that cause respiratory depression such as opioids.5–9
Benzodiazepines have been the focus of research related to the harm of coprescribing sedatives and opioids, but it is important to note that all three classes of sedative hypnotics enact their sedative properties through similar mechanisms.10 11 Benzodiazepines, barbiturates and z-drugs are gamma-aminobutyric acid-A receptor agonists and can increase the frequency and time of ion channel openings.12–14 This can lead to CNS depression, presenting the risk of respiratory depression, prolonged sedation, falls risk and death which is only heightened with the addition of opioids.15–18 Moreover, the concomitant use of opioids and sedatives can increase the risk of overdose, hospitalisations, emergency visits and mortality.19–21
Patients over 65 years of age, individuals with musculoskeletal pain and those who have mental health comorbidities are examples of patient groups that are commonly seen to be coprescribed with opioids and sedatives.22–24 Additionally, the sedative and opioids might be coprescribed for individuals suffering from conditions such as insomnia or emotional distress, precipitated by uncontrolled pain.25–28 However, there has been a push to educate providers and move away from coprescribing these medications. In 2016, the Food and Drug Administration (FDA) instituted a required ‘black box’ warning on prescription benzodiazepines and opioids that warns of the dangers of coprescribing these two drug classes.29 In that same year, the opioid prescribing guidelines published by the Centers for Disease Control and Prevention (CDC) released recommendations for clinicians to avoid prescribing benzodiazepines with opioids.30 Moreover, the FDA released black box warnings about the serious health risks associated with concomitant use of benzodiazepines with opioids.31 This, in turn, has resulted in studies that have shown a recent decrease in coprescribing of opioids and benzodiazepines.32 33 However, coprescribing remains prevalent and requires attention.34 The benzodiazepines and opioids coprescriptions rate increased by 41% during 2002–2014.35 Although the coprescribing rates for opioids and sedatives have declined between 2010 and 2018, about 23% of opioid users still received sedatives. About 86% of 12 000 benzodiazepine overdose-related deaths in 2020 involved coprescription of opioids.36 Moreover, there are sedatives, other than benzodiazepines, that are frequently used with opioids and present similar health risks including overdose-related risks.34 However, there are no clear recommendations for other sedatives. While the CDC guidelines recommend weighing risks versus benefits,37 there are no warnings issued by the FDA for sedatives other than benzodiazepines.31 Since these sedatives are used frequently and can present similar CNS and respiratory risks when used with opioids, there is a need to understand how clinicians are coprescribing sedatives other than benzodiazepines. Thus, it is equally important to understand the coprescribing patterns of all three types of sedatives with opioids. The objective of this study was to evaluate the trends in the sedatives (benzodiazepines, barbiturates and z-drugs) being coprescribed with opioids, describe the characteristics of patients who were coprescribed sedatives and opioids and describe a time frame in which initial coprescribing occurs.
Methods
Data source
Data for this study were obtained from the Merative MarketScan Commercial Claims and Encounters Database between the years 2005 and 2018. This database provides access to a detailed patient-level information which includes inpatient claims, outpatient claims, procedural claims, outpatient pharmaceutical claims and enrolment information. This data source was selected due to its wide reach of health data which cover active employees and their dependents, early retirees and Consolidated Omnibus Budget Reconciliation Act continues of 250 major employers and health plans. Overall, the total coverage of this data spans the USA and covers around 30 million individuals every year. The data provided were deidentified and followed privacy standards set by the Health Insurance Portability and Accountability Act. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology guideline in the study reporting.
Study design
A retrospective cohort design observing incident prescribing of opioids in individuals receiving incident prescription sedatives was employed. We used Outpatient Pharmaceutical Claims file to identify the prescription and date of prescription for sedatives and opioids. The incident prescription was defined as a prescription with no previous transaction within the same drug class within a year (365 days).38 The index date was defined as the day an individual received their first sedative prescription. Individuals who received sedatives or an opioid in the 365 days preceding the index date were excluded from this cohort. In our definition of sedatives, we included benzodiazepines, barbiturates and z-drugs (zolpidem, zaleplon and eszopiclone).39 Opioids eligible for inclusion in this study were codeine, morphine, oxycodone, hydrocodone, tramadol, buprenorphine, fentanyl, butorphanol, methadone, sufentanil, dihydrocodeine, hydromorphone, levorphanol, meperidine, nalbuphine, opium, oxymorphone, pentazocine, propoxyphene, remifentanil, tapentadol and alfentanil except opioid cold cough medicines.40 We used RxNav, a database of all current and former national drug codes, to make finder files including all classified sedative and opioids national drug codes. The observation period for individuals selected was 12 months prior to and after the index date.
Participants
Patients were eligible for inclusion if they met the following criteria: (1) new claim for prescription sedatives (benzodiazepine, barbiturates or z-drug) being filled, (2) continuous enrolment in the insurance plan for at least 1 year prior to and 1 year after the index date,41 42 (3) complete prescription drug claim records under the insurance plan for at least 1 year prior to the index date through 1 year after the index date, (4) no opioid or sedative prescription(s) within 1 year prior to the index date and (5) individuals aged 18 years or older.
Patient and public involvement
Patients and the public were not involved in this study.
Measures
Outcome measures
The outcome measure of interest for this study is coprescribing of sedatives (benzodiazepines, barbiturates and z-drugs) with opioids. This study employed an incident user design evaluating patients who received prescription sedatives and who then also received incident prescription opioids. For a patient to be considered coprescribed, the opioid would have to be filled within 1 year (365 days) from the index date.42
Other measures
Comorbidity index
The Quan modification of the Charlson Comorbidity Index (QCI) was used to assess comorbidity burden based on the presence of single inpatient or outpatient claims for each of the conditions in the 12-month preindex period.43 Diagnoses were weighted according to QCI scoring and were categorised as QCI scores of 0, 1, 2 or ≥3.
Prior psychiatric conditions
Further evaluation was conducted on specific psychiatric-related conditions from inpatient and outpatient claims within a year from the filling of a sedative prescription. International Classification of Diseases (ICD)-9 and ICD-10 diagnosis codes were used to identify anxiety, depression, severe mental illness and substance use disorder (please refer online supplemental appendix, table A1 for details on diagnosis codes). Patients with at least one claim indicating the above conditions during the 1 year before the index date were considered to have the respective condition. This information was collected to evaluate whether there was an association between coprescribing and specific mental health conditions.
Supplemental material
Other characteristics
Baseline characteristics included age, gender, region of residence and year of index date. Patients with incident sedative and opioid use were identified by prescription insurance claims data showing the medication was filled. Coprescribing was determined by comparing the index date and the date on which the opioid prescription was filled. Individuals who were coprescribed were categorised as either same pharmacy (received opioids at the same pharmacy where the sedative was received) or a different pharmacy. Coprescribing was also categorised by the time frame in which the coprescribing of sedative and opioids took place, either the same day (day 0) or any other day (days 1–365).
Analytical strategies
Bivariate statistics were used to evaluate any factors that may be associated with incident sedative use and incident coprescribing of opioids. A multivariable logistic regression model was constructed, using all patients who were coprescribed, to evaluate the association between patient characteristics and their likelihood of being coprescribed sedatives and opioids. Among individuals who were identified as being coprescribed sedative and opioids, we further evaluated the day of coprescribing to understand clinicians prescribing (eg, physician, other prescriber) and dispensing (eg, pharmacist) practices. Coprescribing day was defined as the day when patients with index sedative prescriptions were coprescribed opioids We evaluated the same day coprescribing and all other days of coprescribing. If patients are receiving both medication classes on the same day, that would indicate the highest likelihood of identifying potentially inappropriate therapy combinations.
Results
A total of 2 632 622 individuals who received a prescription for a sedative between 2005 and 2018 were included in the final cohort. The mean age of this cohort was 43.2 years, and 62.5% of the patients were female. Patients from the South region of the USA made up the largest portion (42.2%) of the cohort (table 1). The QCI comorbidity index score was found to be zero in most individuals (94.9%). Observation of individual comorbidities displayed that 12.3% had anxiety while 9.9% had depression (table 1).
Table 1
Patient characteristics and comorbidities stratified by coprescribing
Among the patients who were prescribed sedatives on the index date, benzodiazepines were the most prescribed sedative at 71.1%, followed by z-drugs at 19.9% and barbiturates at 9%. From 2005 to 2018, the percentage of patients receiving benzodiazepines has continuously increased from 64% to 79.8%, while z-drugs have decreased from 27.7% to 11.2%. Barbiturates prescribing remained relatively unchanged (figure 1).
Figure 1
Sedative drug classes by index year.
Of the full cohort, 557 845 (21.2%) patients were coprescribed opioids in addition to their sedative. The proportion of coprescribed opioids initially increased before starting to decline in 2008 (online supplemental appendix figure A1). Bivariate analyses showed that patients prescribed sedatives only were more likely to be females (62.5% vs 60.2%, p<0.001), individuals from the Northeast region (16.5% vs 11%, p<0.001), as well as those with anxiety (12.3% vs 7.4%, p<0.001), depression (9.9% vs 7.6%, p<0.001) and severe mental illness (1.9% vs 1.4%, p<0.001) when compared with those prescribed sedatives with opioids. Full bivariate comparisons are listed in table 1.
Of those sedative users who were coprescribed an opioid prescription, 59.2% initiated opioid pharmacotherapy on the day they received their incident sedative prescription (table 2). We further reviewed those who were coprescribed to determine whether they were filled at the same or a different pharmacy. However, roughly 60% of the data were missing due to a lack of pharmacy ID reporting in the claims data. Among those with complete pharmacy identifiers, 87.6% of the coprescribed received both medications at the same pharmacy.
Table 2
Day in which new opioid prescription occurred among patients with coprescribing sedative and opioid prescriptions
Multivariable logistic regression was used to identify predictors of coprescribing (table 3). Individuals who were from the South (Adjusted Odds Ratio(aOR) 1.73; 95% CI 1.71 to 1.74), had a Comorbidity Index Score of 1, 2 or ≥3 (aOR 1.19; 95% CI 1.17 to 1.21), (aOR 1.17 (95% CI 1.14 to 1.19)), (aOR 1.25 (95% CI 1.20 to 1.31)) or had a past-year history of substance use disorder (aOR 1.21; 95% CI 1.19 to 1.23) were more likely to receive an opioid prescription within 1 year after their initial sedative prescription. Female patients (aOR 0.93; 95% CI 0.92 to 0.94) who had anxiety (aOR 0.54; 90% CI 0.53 to 0.55), depression (aOR 0.84, 95% CI 0.83 to 0.85), several mental illnesses (aOR 0.80, 95% CI 0.78 to 0.82) and those prescribed a barbiturate (aOR 0.3; 95% CI 0.29 to 0.31) or z-drugs (aOR 0.67; 95% CI 0.66 to 0.68) were less likely to receive both these prescriptions.
Table 3
Parameter estimates from fitted logistic regression model for coprescribing
A second multivariable logistic regression model for coprescribing on the index date was performed (table 4). The results of this model showed that females were less likely to be coprescribed sedatives on the index date of opioid prescribing (aOR 0.89; 95% CI 0.88 to 0.90). Regional data suggest that patients located in the West were more likely to be coprescribed on the index date (aOR 1.49; 95% CI 1.45 to 1.52). Individuals with a QCI score of 0 were more likely to be coprescribed on the index date as compared with patients with a comorbidity index score of 1 or more, as well as anyone with a mental health-related comorbidity. Lastly, evaluation of sedative type shows that individuals who were prescribed either a barbiturate (aOR 0.26; 95% CI 0.25 to 0.27) or a z-drug (aOR 0.32; 95% CI 0.31 to 0.32) were less likely to be coprescribed on the index date compared with benzodiazepines.
Table 4
Parameter estimates from fitted logistic regression model for coprescribing on the index date
Discussion
The requirements and recommendations set forth by the FDA and CDC back in 2016 put a spotlight on the risk involved with coprescribing benzodiazepines and opioids. Since then, there have been studies showing a decline in coprescribing benzodiazepines and opioids.32 33 In our study, benzodiazepines made up the largest proportion of sedatives being prescribed, potentially reflecting the decision to emphasise the risk of coprescribing this medication with opioids. However, barbiturates and z-drugs made up 28.9% of sedative use over the course of our study. Given the size of this cohort, this is still a considerable number of patients who received non-benzodiazepine sedative coprescribing and should be taken into consideration. Including all three medication classes when describing the risks of sedatives prescribed with opioids would be an important improvement to the operational definitions currently being used in substance misuse literature. This study evaluated the coprescription patterns over 2005–2018 study period and found an association between coprescribing and patient characteristics such as gender, comorbidities and mental health conditions.
This study found that one in five patients who received sedatives also received opioid prescriptions which aligns with prior studies.35 36 However, these prior studies examined either coprescriptions patterns among incident opioid patients who received opioids as index drug36 or focused on benzodiazepines.35 Our study cohort included patients with three main types of sedatives (benzodiazepines, barbiturates and z-drugs). Furthermore, our study found that coprescription with opioids showed a gradual decline after 2008 which aligns with findings from previous similar studies.36 44 Since this study examined individuals who had not received opioids in the year prior to the index date, we were able to provide insight on patients who were recently coprescribed opioids and sedatives as compared with individuals who may have been on the combination long term.
Similar to findings from a prior study analysing opioids and benzodiazepines coprescribing trend,35 this study also found that a little over half of the patients who were coprescribed received both prescriptions on the same day. Moreover, our data show that vast majority of patients who were coprescribed received both medications on the same day received them from the same pharmacy. This would indicate that the two medications were knowingly prescribed by the patient’s provider and likely filled by their pharmacist at the same time. Further studies will be needed to understand the factors that play a role in the decision to prescribe and fill these medications together. However, our findings should be interpreted with caution because there is a possibility of selection bias in this study subsample.
This study found that female sedative users were less likely to be coprescribed with opioids. This finding contrasts with prior findings.35 36 44 This could be due to differences in the index drugs used in these studies. We created the study cohort by including patients who had sedatives as index drug and were coprescribed opioids within a year of the first sedative prescription. this study compared associations between coprescribing and comorbidities, including mental health comorbidities. Our study found that an individual with a comorbidity index value was more likely to have been coprescribed than a patient having no comorbidities. However, we found that patients with mental health-related comorbidities were less likely to be coprescribed sedatives and opioids. This differs from the results of another recent study which showed an increased rate of coprescribing in patients with comorbidities such as anxiety, depression and severe mental illness.36 However, our findings of higher likelihood of patients with substance use disorder being coprescribed sedatives and opioids align with the Hartung et al study.36 However, it is noted that this is not an all-encompassing summary of all the conditions that could be associated with coprescribing. For example, this study did not account for conditions such as insomnia, pain and cancer which have all been mentioned in previous studies as potential reasons for prescribing both a sedative and opioid.
Limitations exist for this study. One of the limitations would be the large portion of missing data seen in the analysis of which pharmacies filled both sedatives and opioids for a patient (60%), opening up a potential risk of selection bias. Lastly, it is important to note that the study time frame only extends 1 year after the initial release of the FDA and CDC’s guidance on sedative and opioid prescribing. Moreover, the CDC recently updated opioid prescribing guidelines in 2022 with a slight change in recommendations from avoidance of coprescribing to recommendations to take special precautions when coprescribing benzodiazepines with opioids.37 Even though this CDC 2022 update does not apply to our study because our study period is from 2010 to 2018, it is disconcerting that coprescribing of other sedatives are still being ignored. It could be argued that the data in this study may not provide enough time to establish the true impact of these recommendations on prescribing trends over time. Measurement bias may play a factor in this study given that basic information about patients is readily available through claims data during the selection process. However, the fact that this study uses a very specific population (all individuals who have already received sedatives), bias due to selection is minimised. Lastly, this study provides a large data sample taken from a nationwide claims database of individuals with private insurance. This ensures that the tests being conducted are representative of the whole country. Additionally, the time frame of this study spans 12 years and provides enough time to visualise trends in prescribing. Finally, due to data limitation, we could not account for socioeconomic factors such as race, income level and place of residence that could potentially influence coprescribing of sedatives and opioids.
Conclusion
Our study analysed coprescribing of sedatives and opioids has shown a gradual decline over the 2005–2018 study period. Patient characteristics such as gender, comorbidities, mental health conditions and substance use disorder were associated with coprescribing of sedatives and opioids. While previous federal guidance has focused on the potential dangers associated with coprescribing benzodiazepine and opioids, coprescribing with benzodiazepines as well as barbiturates and z-drugs is still commonly occurring. This indicates there is still a need to broaden the focus towards risks associated with coprescribing benzodiazepines and non-benzodiazepine sedative medications. As the attention expands towards all sedatives, there will also need to be more dialogue regarding the circumstances that lead to coprescribing of these medications. Using this information, the emphasis will need to shift towards alternative strategies to manage instances that have previously warranted coprescribing of sedatives and opioids.
Data availability statement
Data may be obtained from a third party and are not publicly available. Data included in this study are restricted to access data files.
Ethics statements
Patient consent for publication
Ethics approval
The MarketScan research data files used in this study are fully compliant with privacy standards set by the Health Insurance Portability and Accountability Act and the Institutional Review Board review was waived.
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