Skip to main content

Advertisement

SpringerLink
Log in

Risk of cardiovascular events according to the tricyclic antidepressant dosage in patients with chronic pain: a retrospective cohort study

  • Research
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

We aimed to examine the risk of cardiovascular adverse events by tricyclic antidepressant (TCA) dosage among patients with chronic pain.

Methods

A retrospective cohort study was conducted using a nationwide sample cohort. Among patients aged ≥ 18 years with a chronic pain diagnosis and no history of cardiovascular events, we extracted users and non-users of TCAs through 1:1 propensity score matching. TCA users were categorized into three groups according to the mean defined daily dose (DDD): very low doses (< 0.15 DDD), low doses (0.15–0.34 DDD), and traditional doses (≥ 0.34 DDD). A 6-month follow-up was conducted with an intention-to-treat approach. We examined the hazard ratio of cardiovascular adverse events using Cox proportional hazards analysis.

Results

In total, 16,660 matched patients were followed up (8330 TCA users and 8330 non-users). TCA use did not significantly increase cardiovascular adverse events (hazard ratio [HR] 1.12, 95% confidence interval [CI] 0.94–1.33). Low-dose (0.15–0.34 DDD) TCAs (HR 1.37, 95% CI 1.08–1.74), particularly low-dose (0.15–0.34 DDD) nortriptyline (HR 2.11, 95% CI 1.44–3.08), was associated with an increased risk of cardiovascular adverse events. Administration of TCAs at the traditional dose (≥ 0.34 DDD) increased the risk of ischemic stroke (HR 2.08, 95% CI 1.11–3.88).

Conclusion

Close monitoring of patients on long-term, low-dose use of TCAs should be conducted to avoid an increase in the cumulative dose, which increases the risk of cardiovascular adverse events.

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
Fig. 4

Similar content being viewed by others

Availability of data and materials

Not applicable.

References

  1. Clauw DJ, Essex MN, Pitman V, Jones KD (2019) Reframing chronic pain as a disease, not a symptom: rationale and implications for pain management. Postgrad Med 131:185–198

    Article  Google Scholar 

  2. Treede RD, Rief W, Barke A, Aziz Q, Bennett MI, Benoliel R et al (2019) Chronic pain as a symptom or a disease: the IASP classification of chronic pain for the International Classification of Diseases (ICD-11). Pain 160:19–27

    Article  Google Scholar 

  3. Finnerup NB, Attal N, Haroutounian S, McNicol E, Baron R, Dworkin RH et al (2015) Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis. Lancet Neurol 14:162–173

    Article  CAS  Google Scholar 

  4. Becker WJ, Findlay T, Moga C, Scott NA, Harstall C, Taenzer P (2015) Guideline for primary care management of headache in adults. Can Fam Physician 61:670–679

    Google Scholar 

  5. Urquhart DM, Wluka AE, van Tulder M, Heritier S, Forbes A, Fong C et al (2018) Efficacy of low-dose amitriptyline for chronic low back pain: a randomized clinical trial. JAMA Intern Med 178:1474–1481

    Article  Google Scholar 

  6. Maarrawi J, Abdel Hay J, Kobaiter-Maarrawi S, Tabet P, Peyron R, Garcia-Larrea L (2018) Randomized double-blind controlled study of bedtime low-dose amitriptyline in chronic neck pain. Eur J Pain 22:1180–1187

    Article  CAS  Google Scholar 

  7. Park SW, Lee H, Lee HJ, Park JC, Shin SK, Lee SK et al (2013) Low-dose amitriptyline combined with proton pump inhibitor for functional chest pain. World J Gastroenterol 19:4958–4965

    Article  Google Scholar 

  8. Dharmshaktu P, Tayal V, Kalra BS (2012) Efficacy of antidepressants as analgesics: a review. J Clin Pharmacol 52:6–17

    Article  CAS  Google Scholar 

  9. Vieweg WVR, Wood MA (2004) Tricyclic antidepressants, QT interval prolongation, and torsade de pointes. Psychosomatics 45:371–377

    Article  CAS  Google Scholar 

  10. Zemrak WR, Kenna GA (2008) Association of antipsychotic and antidepressant drugs with QT interval prolongation. Am J Health Syst Pharm 65:1029–1038

    Article  CAS  Google Scholar 

  11. Lee YC, Lin CH, Lin MS, Lin JW, Chang CH, Lai MS (2013) Effects of selective serotonin reuptake inhibitors versus tricyclic antidepressants on cerebrovascular events: a nationwide population-based cohort study. J Clin Psychopharmacol 33:782–789

    Article  CAS  Google Scholar 

  12. Weeke P, Jensen A, Folke F, Gislason GH, Olesen JB, Andersson C et al (2012) Antidepressant use and risk of out-of-hospital cardiac arrest: a nationwide case–time–control study. Clin Pharmacol Ther 92:72–79

    Article  CAS  Google Scholar 

  13. Jang HY, Kim JH, Song YK, Shin JY, Lee HY, Ahn YM et al (2020) Antidepressant use and the risk of major adverse cardiovascular events in patients without known cardiovascular disease: a retrospective cohort study. Front Pharmacol 2103

  14. Coupland C, Hill T, Morriss R, Moore M, Arthur A, Hippisley-Cox J (2016) Antidepressant use and risk of cardiovascular outcomes in people aged 20 to 64: cohort study using primary care database. BMJ 352:i1350

    Article  Google Scholar 

  15. Uusvaara J, Pitkala KH, Kautiainen H, Tilvis RS, Strandberg TE (2011) Association of anticholinergic drugs with hospitalization and mortality among older cardiovascular patients: a prospective study. Drugs Aging 28:131–138

    Article  CAS  Google Scholar 

  16. Glassman AH, Roose SP, Bigger JT (1993) The safety of tricyclic antidepressants in cardiac patients: risk-benefit reconsidered. JAMA 269:2673–2675

    Article  CAS  Google Scholar 

  17. Park HJ, Moon DE (2010) Pharmacologic management of chronic pain. Korean J Pain 23:99–108

    Article  CAS  Google Scholar 

  18. Moore A, Aldington D (2017) Low dose imipramine for multiple functional somatic syndromes. Lancet Psychiatry 4:349–351

    Article  Google Scholar 

  19. Berg J (2004) Economic evidence in migraine and other headaches: a review. Eur J Health Econ: HEPAC 5:S43.

  20. Koo H, Lee MT, You SH, Seon JY, Lee S, Jeong KH et al (2020) Duplicated tramadol use in chronic low back pain: a nationwide cross-sectional study. Basic Clin Pharmacol Toxicol 126:226–235

    Article  CAS  Google Scholar 

  21. Moon SS, Kim CH, Kang SM, Kim ES, Oh TJ, Yun JS et al (2021) Status of diabetic neuropathy in Korea: a National Health Insurance Service-national sample cohort analysis (2006 to 2015). Diabetes Metab J 45:115–119

    Article  Google Scholar 

  22. Mayhew M, DeBar LL, Deyo RA, Kerns RD, Goulet JL, Brandt CA et al (2019) Development and assessment of a crosswalk between ICD-9-CM and ICD-10-CM to identify patients with common pain conditions. J Pain 20:1429–1445

    Article  Google Scholar 

  23. Zinboonyahgoon N, Luansritisakul C, Eiamtanasate S, Duangburong S, Sanansilp V, Korwisi B et al (2021) Comparing the ICD-11 chronic pain classification with ICD-10: how can the new coding system make chronic pain visible? A study in a tertiary care pain clinic setting. Pain 162:1995–2001

    Article  CAS  Google Scholar 

  24. Schrepf A, Phan V, Clemens JQ, Maixner W, Hanauer D, Williams DA (2020) ICD-10 codes for the study of chronic overlapping pain conditions in administrative databases. J Pain 21:59–70

    Article  Google Scholar 

  25. Smith HJ, Taubman SB, Clark LL (2020) A burden and prevalence analysis of chronic pain by distinct case definitions among active duty US military service members, 2018. Pain Phys 23:E429–E440

    Article  Google Scholar 

  26. Ou LB, Azoulay L, Reynier P et al (2021) Tramadol versus codeine and the short-term risk of cardiovascular events in patients with non-cancer pain: a population-based cohort study. Br J Clin Pharmacol 88:1824–1834

    Article  Google Scholar 

  27. World Health Organization (2022) Guidelines for ATC Classification and DDD Assignment. Available at: https://www.whocc.no/filearchive/publications/2022_guidelines_web.pdf. (Accessed 26 Feb 2022)

  28. Doyle Strauss L, Weizenbaum E, Loder EW, Rizzoli PB (2016) Amitriptyline dose and treatment outcomes in specialty headache practice: a retrospective cohort study. Headache 56:1626–1634

    Article  Google Scholar 

  29. Kamble SV, Motlekar SA, D’souza LL, Kudrigikar VN, Rao SE (2017) Low doses of amitriptyline, pregabalin, and gabapentin are preferred for management of neuropathic pain in India: is there a need for revisiting dosing recommendations? The Korean J Pain 30:183–191

    Article  CAS  Google Scholar 

  30. Quan H et al (2005) Coding algorithms for defining comorbidities in ICD-9-CM and ICD-10 administrative data. Medical Care 1130–1139

  31. Lee Y, Park S, Lee S, Kim Y, Kang MW, Cho S et al (2020) Lipid profiles and risk of major adverse cardiovascular events in CKD and diabetes: a nationwide population-based study. PLoS ONE 15:e0231328

    Article  CAS  Google Scholar 

  32. Jeong HE, Oh IS, Kim WJ, Shin JY (2020) Risk of major adverse cardiovascular events associated with concomitant use of antidepressants and non-steroidal anti-inflammatory drugs: a retrospective cohort study. CNS Drugs 34:1063–1074

    Article  CAS  Google Scholar 

  33. Krämer LV, Mueller-Weinitschke C, Zeiss T, Baumeister H, Ebert DD, Bengel J (2022) Effectiveness of a web-based behavioural activation intervention for individuals with depression based on the Health Action Process Approach: protocol for a randomised controlled trial with a 6-month follow-up. BMJ Open 12:e054775

    Article  Google Scholar 

  34. Wallis CJ, Lee LY, Krakowsky Y et al (2016) Survival and cardiovascular events in men treated with testosterone replacement therapy: an intention-to-treat observational cohort study. Lancet DiabetesEndocrinol 4(6):498–506

    CAS  Google Scholar 

  35. Lin DY, Wei LJ, Ying Z (1993) Checking the Cox model with cumulative sums of martingale-based residuals. Biometrics 80(3):557–572

    Article  Google Scholar 

  36. Truven Health Analytics Micromedex® Solutions Dosing/Administration. Available at: http://www.micromedexsolutions.com. (Accessed 10 May 2022).

  37. Health Insurance Review and Assessment Service. Notification No. 2018–18 (Pharmaceuticals). Available at: http://www.hira.or.kr/rd/insuadtcrtr/InsuAdtCrtrPopup.do?mtgHmeDd=20180201&sno=1&mtgMtrRegSno=0006. (Accessed 5 May 2022)

  38. Mars B, Heron J, Kessler D, Davies NM, Martin RM, Thomas KH et al (2017) Influences on antidepressant prescribing trends in the UK: 1995–2011. Soc Psychiatry Psychiatr Epidemiol 52:193–200

    Article  Google Scholar 

  39. Juang HT, Chen PC, Chien KL (2015) Using antidepressants and the risk of stroke recurrence: report from a national representative cohort study. BMC Neurol 15:86

    Article  Google Scholar 

  40. Kim JH, Song YK, Jang HY, Shin JY, Lee HY, Ahn YM et al (2020) Major adverse cardiovascular events in antidepressant users within patients with ischemic heart diseases: a nationwide cohort study. J Clin Psychopharmacol 40:475–481

    Article  Google Scholar 

  41. Royds J, Conroy MJ, Dunne MR, McCrory C, Lysaght J (2020) An investigation into the modulation of T cell phenotypes by amitriptyline and nortriptyline. Eur Neuropsychopharmacol 31:131–144

    Article  CAS  Google Scholar 

  42. Ozmen MC, Dieckmann G, Cox SM, Rashad R, Paracha R, Sanayei N et al (2020) Efficacy and tolerability of nortriptyline in the management of neuropathic corneal pain. Ocul Surf 18:814–820

    Article  Google Scholar 

  43. Alvarez W Jr, Pickworth KK (2003) Safety of antidepressant drugs in the patient with cardiac disease: a review of the literature. Pharmacotherapy 23:754–771

    Article  CAS  Google Scholar 

  44. Bardai A, Amin AS, Blom MT, Bezzina CR, Berdowski J, Langendijk PN et al (2013) Sudden cardiac arrest associated with use of a non-cardiac drug that reduces cardiac excitability: evidence from bench, bedside, and community. Eur Heart J 34:1506–1516

    Article  CAS  Google Scholar 

  45. Woodward M (2019) Cardiovascular disease and the female disadvantage. Int J Environ Res Public Health 16:1165

    Article  Google Scholar 

  46. Ray WA, Meredith S, Thapa PB, Hall K, Murray KT (2004) Cyclic antidepressants and the risk of sudden cardiac death. Clin Pharmacol Ther 75:234–241

    Article  CAS  Google Scholar 

  47. White WB (2007) Cardiovascular risk, hypertension, and NSAIDs. Curr Rheumatol Rep 9(1):36–43

  48. Leong C, Alessi-Severini S, Enns MW et al (2017) Cerebrovascular, cardiovascular, and mortality events in new users of selective serotonin reuptake inhibitors and serotonin norepinephrine reuptake inhibitors: a propensity score-matched population-based study. J Clin Psychopharmacol 37(3):332–340

    Article  CAS  Google Scholar 

  49. Roberto G, Raschi E, Piccinni C et al (2015) Adverse cardiovascular events associated with triptans and ergotamines for treatment of migraine: systematic review of observational studies. Cephalalgia 35(2):118–131

    Article  CAS  Google Scholar 

  50. Hernán MA, Alonso A, Logan R, Grodstein F, Michels KB, Willett WC et al (2008) Observational studies analyzed like randomized experiments: an application to postmenopausal hormone therapy and coronary heart disease. Epidemiol (Camb Mass) 19:766–779

    Article  Google Scholar 

  51. Patorno E, Htoo PT, Glynn RJ, Schneeweiss S, Wexler DJ, Pawar A et al (2021) Sodium–glucose cotransporter-2 inhibitors versus glucagon-like peptide-1 receptor agonists and the risk for cardiovascular outcomes in routine care patients with diabetes across categories of cardiovascular disease. Ann Intern Med 174:1528–1541

    Article  Google Scholar 

  52. Keto J, Ventola H, Jokelainen J, Linden K, Keinänen-Kiukaanniemi S, Timonen M et al (2016) Cardiovascular disease risk factors in relation to smoking behaviour and history: a population-based cohort study. Open Heart 3:e000358

    Article  Google Scholar 

  53. Liu Y, Xu X, Dong M, Jia S, Wei Y (2017) Treatment of insomnia with tricyclic antidepressants: a meta-analysis of polysomnographic randomized controlled trials. Sleep Med 34:126–133

    Article  Google Scholar 

Download references

Acknowledgements

This study used the National Health Insurance Service–National Sample Cohort (NHIS-NSC) data (NHIS-2020-2-092) made available by the NHIS.

Author information

Authors and Affiliations

  1. College of Pharmacy, Chung-Ang University, 84 Heukseok-Ro, Dongjak-Gu, Seoul, 06974, Republic of Korea

    Hyunji Koo, Kyeong Hye Jeong & Sun-Young Jung

  2. Department of Global Innovative Drugs, Graduate School of Chung-Ang University, Chung-Ang University, Seoul, South Korea

    Seung Hun You, Sewon Park & Sun-Young Jung

  3. College of Pharmacy, Pusan National University College of Pharmacy, Pusan, South Korea

    Nakyung Jeon

Authors
  1. Hyunji Koo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Seung Hun You
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sewon Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kyeong Hye Jeong
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Nakyung Jeon
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Sun-Young Jung
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors contributed to the study’s conception and design. Material preparation, data collection, and analysis were performed by Sun-Young Jung, Seung Hun You, and Hyunji Koo. The first draft of the manuscript was written by Hyunji Koo. Kyeong Hye Jeong, Nakyung Jeon, Sewon Park, and Sun-Young Jung reviewed and edited previous versions of the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Sun-Young Jung.

Ethics declarations

Ethical approval

This study protocol was exempted from review by the Institutional Review Board of Chung-Ang University (IRB Number: 1041078–202002-HR-022–01).

Consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 132 KB)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Koo, H., You, S.H., Park, S. et al. Risk of cardiovascular events according to the tricyclic antidepressant dosage in patients with chronic pain: a retrospective cohort study. Eur J Clin Pharmacol 79, 159–171 (2023). https://doi.org/10.1007/s00228-022-03421-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00228-022-03421-z

Keywords

Search

Navigation