Skip to main content

Advertisement

SpringerLink
Log in

Concurrent use of benzodiazepines, antidepressants, and opioid analgesics with zolpidem and risk for suicide: a case–control and case–crossover study

  • Original Paper
  • Published:
Social Psychiatry and Psychiatric Epidemiology Aims and scope Submit manuscript

Abstract

Purpose

To evaluate whether the concurrent use of benzodiazepines, antidepressants, and opioid analgesics with zolpidem increases the risk of suicide or triggers suicide compared with the use of zolpidem alone.

Methods

We conducted a case–control and case–crossover study using the Korean National Health Insurance Service-National Sample Cohort database. Cases were older than 20 years with a suicide record (International Codes of Disease 10th Revision codes: X-60-X84 and Y87.0 intentional self-harm) between January 1, 2004, and December 31, 2013. For case–control design, ten controls were matched to each case by age, sex, index year, region, income, and health insurance type. For case–crossover analysis, we set hazard period to 60 days and assigned five corresponding sets of control periods of equal length. Exposure was assessed during 60 days before suicide for combinations of benzodiazepines, antidepressants, opioid analgesics with zolpidem against zolpidem alone. We conducted a conditional logistic regression to estimate odds ratios (ORs) and their 95% confidence intervals (CIs).

Results

In the case–control study, the risk of suicide was 2.80-fold higher in cases taking benzodiazepines and antidepressants with zolpidem than in those taking zolpidem alone (adjusted OR [aOR], 2.80; 95% CI, 1.38–5.70). However, in the case–crossover study, suicide risk showed no significant difference (crude OR [cOR], 0.92; 95% CI, 0.55–1.52) and was underpowered.

Conclusions

The results of the traditional case–control study confirmed that the concurrent use of benzodiazepines and antidepressants with zolpidem was associated with an increased risk of suicide compared with the use of zolpidem alone. However, there was no significant difference in the magnitude of risk in the within-person comparison design.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. de Haas SL, Schoemaker RC, van Gerven JM, Hoever P, Cohen AF, Dingemanse J (2010) Pharmacokinetics, pharmacodynamics and the pharmacokinetic/pharmacodynamic relationship of zolpidem in healthy subjects. J Psychopharmacol 24(11):1619–1629. https://doi.org/10.1177/0269881109106898(Oxford, England)

    Article  PubMed  CAS  Google Scholar 

  2. Baselt RC (2008) Disposition of toxic drugs and chemicals in man, 8th edn. Biomedical Publishers, Foster City, CA

    Google Scholar 

  3. Whyte J, Myers R (2009) Incidence of clinically significant responses to zolpidem among patients with disorders of consciousness: a preliminary placebo controlled trial. Am J Phys Med Rehabil 88(5):410–418. https://doi.org/10.1097/PHM.0b013e3181a0e3a0

    Article  PubMed  Google Scholar 

  4. Darcourt G, Pringuey D, Salliere D, Lavoisy J (1999) The safety and tolerability of zolpidem—an update. J Psychopharmacol 13(1):81–93. https://doi.org/10.1177/026988119901300109(Oxford, England)

    Article  PubMed  CAS  Google Scholar 

  5. Ben-Hamou M, Marshall NS, Grunstein RR, Saini B, Fois RA (2011) Spontaneous adverse event reports associated with zolpidem in Australia 2001–2008. J Sleep Res 20(4):559–568. https://doi.org/10.1111/j.1365-2869.2011.00919.x

    Article  PubMed  Google Scholar 

  6. Bush DM (2013) Emergency department visits attributed to overmedication that involved the insomnia medication zolpidem. In: The CBHSQ report. Substance abuse and mental health services administration (US), Rockville (MD),

  7. McCall WV, Benca RM, Rosenquist PB, Riley MA, McCloud L, Newman JC, Case D, Rumble M, Krystal AD (2017) Hypnotic medications and suicide: risk, mechanisms, mitigation, and the FDA. Am J Psychiatry 174(1):18–25. https://doi.org/10.1176/appi.ajp.2016.16030336

    Article  PubMed  Google Scholar 

  8. Wong CK, Marshall NS, Grunstein RR, Ho SS, Fois RA, Hibbs DE, Hanrahan JR, Saini B (2017) Spontaneous adverse event reports associated with zolpidem in the United States 2003–2012. J Clin Sleep Med 13(2):223–234. https://doi.org/10.5664/jcsm.6452

    Article  PubMed  PubMed Central  Google Scholar 

  9. Tj M (2015) ISMP quarter watch: monitoring FDA MedWatch reports. ISMP, Philadelphia

    Google Scholar 

  10. Mary Ross Southwork-Division of drug risk evaluation (2006) ODS Postmarketing safety review drug(s) zaleplon (20-859)-eszopiclone (21-476)-zolpidem (19-908) Event-suicidal ideation and attempts-completed suicides. Center for Drug Evaluation and Research of the Food and Drug Administration; D050402 D050403 D050404;8-31-2006, Rockville, MD

  11. Lee D, Delcher C, Maldonado-Molina MM, Thogmartin JR, Goldberger BA (2016) Manners of death in drug-related fatalities in Florida. J Forensic Sci 61(3):735–742. https://doi.org/10.1111/1556-4029.12999

    Article  PubMed  CAS  Google Scholar 

  12. Dodds TJ (2017) Prescribed benzodiazepines and suicide risk: a review of the literature. Prim Care Companion CNS Disord. https://doi.org/10.4088/pcc.16r02037

    Article  PubMed  Google Scholar 

  13. Bielefeldt AO, Danborg PB, Gotzsche PC (2016) Precursors to suicidality and violence on antidepressants: systematic review of trials in adult healthy volunteers. J R Soc Med 109(10):381–392. https://doi.org/10.1177/0141076816666805

    Article  PubMed  PubMed Central  Google Scholar 

  14. Ilgen MA, Bohnert AS, Ganoczy D, Bair MJ, McCarthy JF, Blow FC (2016) Opioid dose and risk of suicide. Pain 157(5):1079–1084. https://doi.org/10.1097/j.pain.0000000000000484

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Bertisch SM, Herzig SJ, Winkelman JW, Buettner C (2014) National use of prescription medications for insomnia: NHANES 1999–2010. Sleep 37(2):343–349. https://doi.org/10.5665/sleep.3410

    Article  PubMed  PubMed Central  Google Scholar 

  16. Sun EC, Dixit A, Humphreys K, Darnall BD, Baker LC, Mackey S (2017) Association between concurrent use of prescription opioids and benzodiazepines and overdose: retrospective analysis. BMJ 356:j760. https://doi.org/10.1136/bmj.j760(Clinical research ed)

    Article  PubMed  PubMed Central  Google Scholar 

  17. Turner BJ, Liang Y (2015) Drug overdose in a retrospective cohort with non-cancer pain treated with opioids, antidepressants, and/or sedative-hypnotics: interactions with mental health disorders. J Gen Intern Med 30(8):1081–1096. https://doi.org/10.1007/s11606-015-3199-4

    Article  PubMed  PubMed Central  Google Scholar 

  18. Tsuno N, Besset A, Ritchie K (2005) Sleep and depression. J Clin Psychiatry 66(10):1254–1269

    Article  PubMed  Google Scholar 

  19. Thase ME (2006) Depression and sleep: pathophysiology and treatment. Dialogues Clin Neurosci 8(2):217–226

    PubMed  PubMed Central  Google Scholar 

  20. Amihaesei IC, Mungiu OC (2012) Main neuroendocrine features and therapy in primary sleep troubles. Rev Med Chir Soc Med Nat Iasi 116(3):862–866

    PubMed  Google Scholar 

  21. Niedrig DF, Hoppe L, Machler S, Russmann H, Russmann S (2016) Benzodiazepine use during hospitalization: automated identification of potential medication errors and systematic assessment of preventable adverse events. PLoS One 11(10):e0163224. https://doi.org/10.1371/journal.pone.0163224

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Zin CS, Ismail F (2017) Co-prescription of opioids with benzodiazepine and other co-medications among opioid users: differential in opioid doses. J Pain Res 10:249–257. https://doi.org/10.2147/jpr.s122853

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Geoffroy PA, Hoertel N, Etain B, Bellivier F, Delorme R, Limosin F, Peyre H (2018) Insomnia and hypersomnia in major depressive episode: prevalence, sociodemographic characteristics and psychiatric comorbidity in a population-based study. J Affect Disord 226:132–141. https://doi.org/10.1016/j.jad.2017.09.032

    Article  PubMed  Google Scholar 

  24. Darke S, Deady M, Duflou J (2012) Toxicology and characteristics of deaths involving zolpidem in New South Wales, Australia 2001–2010. J Forensic Sci 57(5):1259–1262. https://doi.org/10.1111/j.1556-4029.2012.02117.x

    Article  PubMed  Google Scholar 

  25. Delaveris GJ, Teige B, Rogde S (2014) Non-natural manners of death among users of illicit drugs: substance findings. Forensic Sci Int 238:16–21. https://doi.org/10.1016/j.forsciint.2014.02.009

    Article  PubMed  CAS  Google Scholar 

  26. Poulter MO, Du L, Weaver IC, Palkovits M, Faludi G, Merali Z, Szyf M, Anisman H (2008) GABAA receptor promoter hypermethylation in suicide brain: implications for the involvement of epigenetic processes. Biol Psychiatry 64(8):645–652. https://doi.org/10.1016/j.biopsych.2008.05.028

    Article  PubMed  CAS  Google Scholar 

  27. Klempan TA, Sequeira A, Canetti L, Lalovic A, Ernst C, Ffrench-Mullen J, Turecki G (2009) Altered expression of genes involved in ATP biosynthesis and GABAergic neurotransmission in the ventral prefrontal cortex of suicides with and without major depression. Mol Psychiatry 14(2):175–189. https://doi.org/10.1038/sj.mp.4002110

    Article  PubMed  CAS  Google Scholar 

  28. Sequeira A, Mamdani F, Ernst C, Vawter MP, Bunney WE, Lebel V, Rehal S, Klempan T, Gratton A, Benkelfat C, Rouleau GA, Mechawar N, Turecki G (2009) Global brain gene expression analysis links glutamatergic and GABAergic alterations to suicide and major depression. PLoS One 4(8):e6585. https://doi.org/10.1371/journal.pone.0006585

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Choudary PV, Molnar M, Evans SJ, Tomita H, Li JZ, Vawter MP, Myers RM, Bunney WE Jr, Akil H, Watson SJ, Jones EG (2005) Altered cortical glutamatergic and GABAergic signal transmission with glial involvement in depression. Proc Natl Acad Sci USA 102(43):15653–15658. https://doi.org/10.1073/pnas.0507901102

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  30. Merali Z, Du L, Hrdina P, Palkovits M, Faludi G, Poulter MO, Anisman H (2004) Dysregulation in the suicide brain: mRNA expression of corticotropin-releasing hormone receptors and GABA(A) receptor subunits in frontal cortical brain region. J Neurosci 24(6):1478–1485. https://doi.org/10.1523/jneurosci.4734-03.2004

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Asberg M, Thoren P, Traskman L, Bertilsson L, Ringberger V (1976) “Serotonin depression”—a biochemical subgroup within the affective disorders? Science 191(4226):478–480 (New York, NY)

    Article  CAS  PubMed  Google Scholar 

  32. Arango V, Underwood MD, Mann JJ (2002) Serotonin brain circuits involved in major depression and suicide. Prog Brain Res 136:443–453

    Article  CAS  PubMed  Google Scholar 

  33. Saltiel PF, Silvershein DI (2015) Major depressive disorder: mechanism-based prescribing for personalized medicine. Neuropsychiatr Dis Treat 11:875–888. https://doi.org/10.2147/ndt.s73261

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Brower KJ, McCammon RJ, Wojnar M, Ilgen MA, Wojnar J, Valenstein M (2011) Prescription sleeping pills, insomnia, and suicidality in the national comorbidity survey replication. J Clin Psychiatry 72(4):515–521. https://doi.org/10.4088/JCP.09m05484gry

    Article  PubMed  Google Scholar 

  35. Sun Y, Lin CC, Lu CJ, Hsu CY, Kao CH (2016) Association between zolpidem and suicide: a nationwide population-based case–control study. Mayo Clin Proc 91(3):308–315. https://doi.org/10.1016/j.mayocp.2015.10.022

    Article  PubMed  CAS  Google Scholar 

  36. Choi B, Sung HG, Nam JH, Shin JY (2019) Zolpidem use and suicide death in South Korea: a population-based case–control study. Suicide Life Threat Behav. https://doi.org/10.1111/sltb.12548

    Article  PubMed  Google Scholar 

  37. Won T, Kang B, Im T, Choi H (2007) The study of accuracy of death statistics (original articles: the study of accuracy of death statistics). J Korean Soc Emerg Med 18(3):256–262

    Google Scholar 

  38. Maclure M (1991) The case–crossover design: a method for studying transient effects on the risk of acute events. Am J Epidemiol 133(2):144–153

    Article  CAS  PubMed  Google Scholar 

  39. Olesen JB, Hansen PR, Erdal J, Abildstrom SZ, Weeke P, Fosbol EL, Poulsen HE, Gislason GH (2010) Antiepileptic drugs and risk of suicide: a nationwide study. Pharmacoepidemiol Drug Saf 19(5):518–524. https://doi.org/10.1002/pds.1932

    Article  PubMed  Google Scholar 

  40. Bjorkenstam C, Moller J, Ringback G, Salmi P, Hallqvist J, Ljung R (2013) An association between initiation of selective serotonin reuptake inhibitors and suicide—a nationwide register-based case–crossover study. PLoS One 8(9):e73973. https://doi.org/10.1371/journal.pone.0073973

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. Bagge CL, Borges G (2017) Acute substance use as a warning sign for suicide attempts: a case–crossover examination of the 48 h prior to a recent suicide attempt. J Clin Psychiatry 78(6):691–696. https://doi.org/10.4088/JCP.15m10541

    Article  PubMed  Google Scholar 

  42. Charlson ME, Pompei P, Ales KL, MacKenzie CR (1987) A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis 40(5):373–383

    Article  CAS  PubMed  Google Scholar 

  43. Maclure M, Mittleman MA (2000) Should we use a case–crossover design? Annu Rev Public Health 21:193–221. https://doi.org/10.1146/annurev.publhealth.21.1.193

    Article  PubMed  CAS  Google Scholar 

  44. Maclure M, Fireman B, Nelson JC, Hua W, Shoaibi A, Paredes A, Madigan D (2012) When should case-only designs be used for safety monitoring of medical products? Pharmacoepidemiol Drug Saf 21(Suppl 1):50–61. https://doi.org/10.1002/pds.2330

    Article  PubMed  Google Scholar 

  45. Neutel CI, Patten SB (1997) Risk of suicide attempts after benzodiazepine and/or antidepressant use. Ann Epidemiol 7(8):568–574

    Article  CAS  PubMed  Google Scholar 

  46. Fontanella CA, Campo JV, Phillips GS, Hiance-Steelesmith DL, Sweeney HA, Tam K, Lehrer D, Klein R, Hurst M (2016) Benzodiazepine use and risk of mortality among patients with schizophrenia: a retrospective longitudinal study. J Clin Psychiatry 77(5):661–667. https://doi.org/10.4088/JCP.15m10271

    Article  PubMed  Google Scholar 

  47. Bouchette D, Quick J (2019) Zolpidem. In: StatPearls. StatPearls Publishing, StatPears Publishing LLC.,Treasure Island, FL

  48. Lee R, Petty F, Coccaro EF (2009) Cerebrospinal fluid GABA concentration: relationship with impulsivity and history of suicidal behavior, but not aggression, in human subjects. J Psychiatr Res 43(4):353–359. https://doi.org/10.1016/j.jpsychires.2008.04.004

    Article  PubMed  Google Scholar 

  49. Turecki G, Brent DA (2016) Suicide and suicidal behaviour. Lancet 387(10024):1227–1239. https://doi.org/10.1016/s0140-6736(15)00234-2(London, England)

    Article  PubMed  Google Scholar 

  50. Hooten WM (2016) Chronic pain and mental health disorders: shared neural mechanisms, epidemiology, and treatment. Mayo Clin Proc 91(7):955–970. https://doi.org/10.1016/j.mayocp.2016.04.029

    Article  PubMed  Google Scholar 

  51. Hooley JM, Franklin JC, Nock MK (2014) Chronic pain and suicide: understanding the association. Curr Pain Headache Rep 18(8):435. https://doi.org/10.1007/s11916-014-0435-2

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

This study used National Health Insurance Service (NHIS)—National Sample Cohort data (REQ 0000006111) made available by the NHIS (http://www.nhis.or.kr). We would like to thank Editage for English proofreading. This research was supported by the Seockchun Research Fund, SKKU-Seockchun-2016, Sungkyunkwan University. This study was presented at the 2018 34th International Conference on Pharmaco-epidemiology and Therapeutic Risk Management in Prague, Czech Republic.

Author information

Authors and Affiliations

  1. School of Pharmacy, Sungkyunkwan University, 2066 Seobu-ro, Jangan-gu, Suwon, Gyeong gi-do, South Korea

    Hi Gin Sung, Junquing Li, Jin Hyun Nam, Dae Yeon Won & Ju-Young Shin

  2. Department of Medicine and Program in Public Heath, University of California, Irvine, CA, USA

    BongKyoo Choi

Authors
  1. Hi Gin Sung
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Junquing Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jin Hyun Nam
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Dae Yeon Won
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. BongKyoo Choi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ju-Young Shin
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors contributed to the study design and interpretation of data. JN and JL had the main responsibility for statistical analysis but all authors contributed. HS, DW, BC, and JS drafted the manuscript, and all authors reviewed and commented on drafts and approved the final manuscript as well as the decision to submit for publication. JS is the guarantor of the study, accepts full responsibility for the research, had access to the data, and controlled the decision to publish.

Corresponding author

Correspondence to Ju-Young Shin.

Ethics declarations

Conflict of interest

The Seockchun Research Fund was not involved in the current study. The authors declare no competing interests, including specific financial interests, relationships, or affiliations, relevant to the subject of this manuscript.

Ethical approval

This study was approved by the Sungkyunkwan University Institutional Review Board (IRB no. 2016-10-015).

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 35 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Sung, H., Li, J., Nam, J. et al. Concurrent use of benzodiazepines, antidepressants, and opioid analgesics with zolpidem and risk for suicide: a case–control and case–crossover study. Soc Psychiatry Psychiatr Epidemiol 54, 1535–1544 (2019). https://doi.org/10.1007/s00127-019-01713-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00127-019-01713-x

Keywords

Search

Navigation