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Risk of Fractures in Older Adults with Chronic Non-cancer Pain Receiving Concurrent Benzodiazepines and Opioids: A Nested Case–Control Study

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Abstract

Objective

The aim of this study was to investigate the relationship between the concurrent use of benzodiazepines and opioids and the risk of fractures in older patients with chronic non-cancer pain.

Methods

Patients with osteoarthritis or low back pain (≥ 65 years of age) included in the Korean National Health Insurance Service–National Sample Cohort database of Korea and with an incident diagnosis of hip, humeral, or forearm fracture between 2011 and 2015 were identified as cases. For each case, four controls were matched for age (within 5 years), sex, and year of cohort entry. We estimated the adjusted odds ratios (aORs) and 95% confidence intervals (CIs) for fractures associated with concurrent use of benzodiazepines and opioids using a conditional logistic regression analysis, adjusting for comorbidities and comedications.

Results

The aOR (95% CI) for the concurrent use of benzodiazepines and opioids was 1.45 (1.22–1.71), compared with those of non-use within 30 days before the index date. The aOR was 1.65 (1.22–2.23) in patients who were continuously receiving benzodiazepines and were newly initiated with concurrent opioids. The aORs for concurrent use were 1.95 (1.39–2.74) and 1.27 (1.03–1.56) in the case of hip fracture and forearm fracture, respectively.

Conclusion

The concurrent use of benzodiazepines and opioids was associated with an increased risk of fractures in older patients with chronic non-cancer pain. Therefore, patients continuously receiving benzodiazepines in whom opioids are newly initiated need careful monitoring, and such combined therapy should be limited to the shortest duration possible.

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Acknowledgements

The authors thank Ji-Hye Seo for her support while developing the research protocol.

Author information

Authors and Affiliations

  1. Department of Global Innovative Drugs, Graduate School of Chung-Ang University, Seoul, Republic of Korea

    Ye-Jin Kang, Min-Taek Lee, Myo-Song Kim, Seung-Hun You, Jae-Eun Lee, Joo-Hyeon Eom & Sun-Young Jung

  2. College of Pharmacy, Chung-Ang University, Seoul, Republic of Korea

    Ye-Jin Kang, Min-Taek Lee, Myo-Song Kim, Seung-Hun You, Jae-Eun Lee, Joo-Hyeon Eom & Sun-Young Jung

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Correspondence to Sun-Young Jung.

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Funding

This research was supported by the Chung-Ang University Graduate Research Scholarship in 2020 and the Basic Science Research Program through the National Research Foundation of Korea (NRF), funded by the Ministry of Education (Grant no. NRF-2017R1D1A1B03032231).

Conflict of interest

Ye-Jin Kang, Min-Taek Lee, Myo-Song Kim, Seung-Hun You, Jae-Eun Lee, Joo-Hyeon Eom, and Sun-Young Jung declare no conflicts of interest.

Ethics approval

The need to obtain informed consent was waived since the database contains de-identified information. The study protocol was exempted from review by the IRB of Chung-Ang University (IRB number: 1041078-201707-HR-137-01).

Consent to participate

Not applicable.

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Not applicable.

Availability of data and material

This database is not publicly available and its use is restricted to users who have gained approval for access from the NHIS. We applied for data access to the NHIS along with the study protocol, and the IRB of the principal investigator’s affiliated institution obtained the approval from the NHIS.

Code availability

Not applicable.

Author contributions

Study conception and design: YJK and SYJ. Acquisition of data: YJK, MSK, SHY, and JEL. Analysis: YJK. Interpretation of the data: YJK, MTL, JHE, and SYJ. Drafting and critical revision of the article: YJK and SYJ. All authors approved the version submitted for publication.

Supplementary Information

Below is the link to the electronic supplementary material.

40266_2021_872_MOESM1_ESM.docx

Online Resource 1 Flow of patients used in this study to determine the effect of benzodiazepines and opioids on the risk of fractures. OA osteoarthritis, LBP low back pain, ICD-10 International Classification of Diseases, Tenth Revision, ICU intensive care unit (DOCX 31 kb)

40266_2021_872_MOESM2_ESM.docx

Online Resource 2 International Classification of Diseases, Tenth Revision (ICD-10), diagnosis codes used in the study cohort (DOCX 17 kb)

40266_2021_872_MOESM3_ESM.docx

Online Resource 3 International Classification of Diseases, Tenth Revision (ICD-10), diagnosis codes associated with all types of fractures (DOCX 18 kb)

Online Resource 4 List of benzodiazepines and opioids (DOCX 20 kb)

40266_2021_872_MOESM5_ESM.docx

Online Resource 5 Odds ratios for the use of benzodiazepines and opioids in relation to the risk of fractures according to the Charlson Comorbidity Index and age. aAdjusted for comorbidities and comedications. bNon-use included those who had no record of the use of BZDs and opioids within 30 days before the index date. cBZDs only included patients who had a prescription of BZDs within 30 days before the index date. dOpioids only included patients who had a prescription of opioids within 30 days before the index date. eBoth BZDs and opioids included patients who had prescriptions of BZDs and opioids within 30 days before the index date. OR odds ratio, BZDs benzodiazepines, CCI Charlson Comorbidity Index, Ref reference (DOCX 23 kb)

40266_2021_872_MOESM6_ESM.docx

Online Resource 6 Odds ratios for the use of benzodiazepines and opioids in relation to the risk of fractures. aAdjusted for comorbidities and comedications. bNon-use included those who had no record of the use of BZDs and opioids within 365 days before the index date. cBZDs only included patients who had a prescription of BZDs within 365 days before the index date. dOpioids only included patients who had a prescription of opioids within 365 days before the index date. eBoth BZDs and opioids included patients who had prescriptions of BZDs and opioids within 365 days before the index date. fCurrent use included use within 30 days before the index date. gRecent use included use during 31–90 days before the index date. hPast use included use during 91–365 days before the index date. OR odds ratio, BZDs benzodiazepines, Ref reference (DOCX 23 kb)

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Kang, YJ., Lee, MT., Kim, MS. et al. Risk of Fractures in Older Adults with Chronic Non-cancer Pain Receiving Concurrent Benzodiazepines and Opioids: A Nested Case–Control Study. Drugs Aging 38, 687–695 (2021). https://doi.org/10.1007/s40266-021-00872-4

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