Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Pharmacogenomic study—A pilot study of the effect of pharmacogenomic phenotypes on the adequate dosing of verapamil for migraine prevention



To investigate factors affecting the efficacy and tolerability of verapamil for migraine prevention using individual pharmacogenomic phenotypes.


Verapamil has a wide range of dosing in headache disorders without reliable tools to predict the optimal doses for an individual.


This is a retrospective chart review examining adults with existing pharmacogenomic reports at Mayo Clinic who had used verapamil for migraine. Effects of six cytochrome P450 phenotypes on the doses of verapamil for migraine prevention were assessed.


Our final analysis included 33 migraine patients (82% with aura). The mean minimum effective and maximum tolerable doses of verapamil were 178.2(20-320) mg and 227.9(20-480) mg. A variety of CYP2C9, CYP2D6, and CYP3A5 phenotypes were found, without significant association with the verapamil doses after adjusting for age, sex, body mass index, and smoking status.


We demonstrated a wide range of effective and tolerable verapamil doses used for migraine in a cohort with various pharmacogenomic phenotypes.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Study subjects identifying process.
Fig. 2: The overall distribution of verapamil dose used in this dataset.

Similar content being viewed by others

Data availability

All data generated or analyzed during this study are included in this published article.


  1. Burch R, Rizzoli P, Loder E. The prevalence and impact of migraine and severe headache in the United States: Updated age, sex, and socioeconomic-specific estimates from government health surveys. Headache. 2021;61:60–8.

    Article  PubMed  Google Scholar 

  2. Collaborators. GDaIIaP. Global, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 1990–2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet. 2016;388:1545–602.

    Article  Google Scholar 

  3. Burch RC, Buse DC, Lipton RB. Migraine: Epidemiology, burden, and comorbidity. Neurol Clin. 2019;37:631–49.

    Article  PubMed  Google Scholar 

  4. Blumenfeld AM, Bloudek LM, Becker WJ, Buse DC, Varon SF, Maglinte GA, et al. Patterns of use and reasons for discontinuation of prophylactic medications for episodic migraine and chronic migraine: results from the second international burden of migraine study (IBMS-II). Headache. 2013;53:644–55.

    Article  PubMed  Google Scholar 

  5. Matharu MS, Boes CJ, Goadsby PJ. Management of trigeminal autonomic cephalgias and hemicrania continua. Drugs. 2003;63:1637–77.

    Article  CAS  PubMed  Google Scholar 

  6. Robbins MS, Starling AJ, Pringsheim TM, Becker WJ, Schwedt TJ. Treatment of Cluster Headache: The American Headache Society Evidence-Based Guidelines. Headache. 2016;56:1093–106.

    Article  PubMed  Google Scholar 

  7. Burch R. Preventive migraine treatment. Continuum. 2021;27:613–32.

    PubMed  Google Scholar 

  8. Wu JW, Yang CP. 2022 Taiwan Guidelines for Preventive Treatment of Migraine. Acta Neurol Taiwan. 2022;31:164–202.

    Google Scholar 

  9. Silberstein SD, Holland S, Freitag F, Dodick DW, Argoff C, Ashman E. Evidence-based guideline update: pharmacologic treatment for episodic migraine prevention in adults: report of the Quality Standards Subcommittee of the American Academy of. Neurol Am Headache Soc Neurol 2012;78:1337–45.

    CAS  Google Scholar 

  10. Kowalska M, Prendecki M, Piekut T, Kozubski W, Dorszewska J. Migraine: Calcium Channels and Glia. Int J Mol Sci. 2021;22:2688.

  11. Di Stefano V, Rispoli MG, Pellegrino N, Graziosi A, Rotondo E, Napoli C, et al. Diagnostic and therapeutic aspects of hemiplegic migraine. J Neurol Neurosurg Psychiatry. 2020;91:764–71.

    Article  PubMed  Google Scholar 

  12. Solomon GD, Steel JG, Spaccavento LJ. Verapamil prophylaxis of migraine. A double-blind, placebo-controlled study. JAMA. 1983;250:2500–2.

    Article  CAS  PubMed  Google Scholar 

  13. Yu W, Horowitz SH. Treatment of sporadic hemiplegic migraine with calcium-channel blocker verapamil. Neurology. 2003;60:120–1.

    Article  PubMed  Google Scholar 

  14. Petersen AS, Barloese MCJ, Snoer A, Soerensen AMS, Jensen RH. Verapamil and cluster headache: still a mystery. a narrative review of efficacy, mechanisms and perspectives. Headache. 2019;59:1198–211.

    Article  PubMed  Google Scholar 

  15. Gabai IJ, Spierings EL. Prophylactic treatment of cluster headache with verapamil. Headache. 1989;29:167–8.

    Article  CAS  PubMed  Google Scholar 

  16. Jónsdóttir M, Meyer JS, Rogers RL. Efficacy, side effects and tolerance compared during headache treatment with three different calcium blockers. Headache. 1987;27:364–9.

    Article  PubMed  Google Scholar 

  17. Fotuhi M, Glaun B, Quan SY, Sofare T. Vestibular migraine: a critical review of treatment trials. J Neurol. 2009;256:711–6.

    Article  PubMed  Google Scholar 

  18. Pomes LM, Guglielmetti M, Bertamino E, Simmaco M, Borro M, Martelletti P. Optimising migraine treatment: from drug-drug interactions to personalized medicine. J Headache Pain. 2019;20:56.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Cutrer FM, Moyer AM, Atkinson EJ, Wang L, Tian S, Wu Y, et al. Genetic variants related to successful migraine prophylaxis with verapamil. Mol Genet Genomic Med. 2021;9:e1680.

  20. Busse D, Cosme J, Beaune P, Kroemer HK, Eichelbaum M. Cytochromes of the P450 2C subfamily are the major enzymes involved in the O-demethylation of verapamil in humans. Naunyn Schmiedebergs Arch Pharm. 1995;353:116–21.

    Article  CAS  Google Scholar 

  21. Jin Y, Wang YH, Miao J, Li L, Kovacs RJ, Marunde R, et al. Cytochrome P450 3A5 genotype is associated with verapamil response in healthy subjects. Clin Pharm Ther. 2007;82:579–85.

    Article  CAS  Google Scholar 

  22. Kroemer HK, Gautier JC, Beaune P, Henderson C, Wolf CR, Eichelbaum M. Identification of P450 enzymes involved in metabolism of verapamil in humans. Naunyn Schmiedebergs Arch Pharm. 1993;348:332–7.

    Article  CAS  Google Scholar 

  23. Tracy TS, Korzekwa KR, Gonzalez FJ, Wainer IW. Cytochrome P450 isoforms involved in metabolism of the enantiomers of verapamil and norverapamil. Br J Clin Pharm. 1999;47:545–52.

    Article  CAS  Google Scholar 

  24. Zhao LM, He XJ, Qiu F, Sun YX, Li-Ling J. Influence of ABCB1 gene polymorphisms on the pharmacokinetics of verapamil among healthy Chinese Han ethnic subjects. Br J Clin Pharm. 2009;68:395–401.

    Article  CAS  Google Scholar 

  25. Borlak J, Walles M, Levsen K, Thum T. Verapamil: metabolism in cultures of primary human coronary arterial endothelial cells. Drug Metab Dispos. 2003;31:888–91.

    Article  CAS  PubMed  Google Scholar 

  26. Zhou Y, Ingelman-Sundberg M, Lauschke VM. Worldwide distribution of Cytochrome P450 Alleles: A meta-analysis of population-scale sequencing projects. Clin Pharm Ther. 2017;102:688–700.

    Article  CAS  Google Scholar 

  27. Amitriptyline [package insert]. Prinston, NJ: Sandoz Inc.; 2014.

  28. PAMELOR® (nortriptyline) [package insert]. Hazelwood, MO: Mallinckrodt Pharmaceuticals; 2019.

  29. EFFEXOR XR® (venlafaxine) [package insert]. Philadelphia, PA: Pfizer; 2021.

  30. Hicks JK, Sangkuhl K, Swen JJ, Ellingrod VL, Müller DJ, Shimoda K, et al. Clinical pharmacogenetics implementation consortium guideline (CPIC) for CYP2D6 and CYP2C19 genotypes and dosing of tricyclic antidepressants: 2016 update. Clin Pharm Ther. 2017;102:37–44.

    Article  CAS  Google Scholar 

  31. Jiang F, Kim HD, Na HS, Lee SY, Seo DW, Choi JY, et al. The influences of CYP2D6 genotypes and drug interactions on the pharmacokinetics of venlafaxine: exploring predictive biomarkers for treatment outcomes. Psychopharmacology. 2015;232:1899–909.

    Article  CAS  PubMed  Google Scholar 

  32. The Royal Dutch Pharmacists Association-Pharmacogenetics Working Group (DPWG). Dutch guidelines August 2019 update.

  33. CALAN® SR (verapamil) [package insert]. New York, NY: Pfizer; 2019.

  34. Fuhr U, Müller-Peltzer H, Kern R, Lopez-Rojas P, Jünemann M, Harder S, et al. Effects of grapefruit juice and smoking on verapamil concentrations in steady state. Eur J Clin Pharm. 2002;58:45–53.

    Article  CAS  Google Scholar 

  35. Benowitz NL, Peng M, Jacob P 3rd. Effects of cigarette smoking and carbon monoxide on chlorzoxazone and caffeine metabolism. Clin Pharm Ther. 2003;74:468–74.

    Article  CAS  Google Scholar 

  36. Bauer M, Karch R, Zeitlinger M, Philippe C, Römermann K, Stanek J, et al. Approaching complete inhibition of P-glycoprotein at the human blood-brain barrier: an (R)-[11C]verapamil PET study. J Cereb Blood Flow Metab. 2015;35:743–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Eriksen MK, Thomsen LL, Olesen J. Sensitivity and specificity of the new international diagnostic criteria for migraine with aura. J Neurol Neurosurg Psychiatry. 2005;76:212–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Kelman L. The aura: a tertiary care study of 952 migraine patients. Cephalalgia. 2004;24:728–34.

    Article  CAS  PubMed  Google Scholar 

Download references



Author information

Authors and Affiliations



Y-CC was responsible for designing the review protocol, screening the patients to identify the final cohort, conducting the chart review, extracting the data, and writing the manuscript. HW and JNM performed the data analysis. CER, AJS and FMC reviewed and provided feedback on the manuscript. CCC was responsible for designing the review protocol, assisting the chart review, and writing the manuscript.

Corresponding author

Correspondence to Yi-Chieh Chen.

Ethics declarations

Competing interests

Dr. Robertson has served on advisory boards for Impel, Linpharma, Satsuma, Biohaven, Eli Lilly, and Lundbeck. She has received research funding from Teva, Pfizer, and Lundbeck. She receives compensation as an author and associate editor of UpToDate. Dr. Starling has received consulting fees from Allergan, Amgen, Axsome Therapeutics, Eli Lilly & Company, Everyday Health, Impel, Lundbeck, Med-IQ, Medscape, Neurolief, Novartis, Satsuma, Teva, and Theranica. Dr. Chiang serves on the advisory board for Satsuma and eNeura. Other authors declare no competing financial interests. This paper did not receive any funding.

Additional information

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

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

Chen, YC., Wang, H., Mandrekar, J.N. et al. Pharmacogenomic study—A pilot study of the effect of pharmacogenomic phenotypes on the adequate dosing of verapamil for migraine prevention. Pharmacogenomics J 24, 11 (2024).

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI:


Quick links