Anxiety and primary headaches

Primary headaches (PH) are among the most common disorders in clinical practice. Despite the development of diagnostic and treatment principles, patient management remains unsatisfactory. Comorbid mental disorders are among the most significant factors complicating timely diagnosis and hindering effective treatment of patients with PH. Anxiety and depression are well-established risk factors for the chronicity of PH, particularly migraine and tension-type headache. They also significantly contribute to the clinical presentation of the disease, altering the headache phenotype and complicating the verification of the type of headache. Furthermore, comorbid mental disorders significantly reduce patients’ quality of life, lead to prolonged persistence of the headache syndrome, and require independent treatment. Among mental disorders, anxiety occupies a leading position not only due to its high prevalence in patients with PH, particularly migraine and tension-type headaches, but also due to the development of specific clinical manifestations and behavioral characteristics, sometimes specific to individual forms of headache. Among the most disabling phenomena for patients is cephalalgophobia, which is particularly characteristic of patients with migraine and significantly impairs their daily functioning. Equally severe in patients with PH are manifestations of kinesiophobia and cognitophobia. Given the significance of anxiety disorders in the development of symptoms and the course of PDPH, the use of anxiolytics in these patients is necessary. The choice of anxiolytic in general clinical practice, especially in patients with comorbidity, is often made in favor of nonbenzodiazepine drugs. Among these, one of the optimal agents is etifoxine, which has polymodal effects, which, when taken into account, may provide advantages for the treatment of patients with PH and comorbid anxiety.

1. Vos T, Lim SS, Abbafati C, Abbas KM, Abbasi M, Abbasifard M et al. Global burden of 369 diseases and injuries in 204 countries and territories, 1990-2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet. 2020;396(10258):1204–1222. https://doi.org/10.1016/S0140-6736(20)30925-9.

2. Buse DC, Manack A, Serrano D, Turkel C, Lipton RB. Sociodemographic and comorbidity profiles of chronic migraine and episodic migraine sufferers. J Neurol Neurosurg Psychiatry. 2010;81(4):428–432. https://doi.org/10.1136/jnnp.2009.192492.

3. Scher AI, Bigal ME, Lipton RB. Comorbidity of migraine. Curr Opin Neurol. 2005;18(3):305–310. https://doi.org/10.1097/01.wco.0000169750.52406.a2.

4. Yu X, Tan G. Role of Psychological Factors in Migraine. Cureus. 2024;16(12):e75858. https://doi.org/10.7759/cureus.75858.

5. Caponnetto V, Deodato M, Robotti M, Koutsokera M, Pozzilli V, Galati C et al. Comorbidities of primary headache disorders: a literature review with meta-analysis. J Headache Pain. 2021;22(1):71. https://doi.org/10.1186/s10194-021-01281-z.

6. Jensen R, Stovner LJ. Epidemiology and comorbidity of headache. Lancet Neurol. 2008;7(4):354–361. https://doi.org/10.1016/S1474-4422(08)70062-0.

7. Tabeeva GR. Anxiety disorders associated with chronic pain. Behavioral Neurology. 2025;(1):12–21. (In Russ.) https://doi.org/10.46393/27129675_2025_1_12-21.

8. Breslau N, Davis GC, Andreski P. Migraine, psychiatric disorders, and suicide attempts: an epidemiologic study of young adults. Psychiatry Res. 1991;37(1):11–23. https://doi.org/10.1016/0165-1781(91)90102-u.

9. Merikangas KR, Angst J, Isler H. Migraine and psychopathology. Results of the Zurich cohort study of young adults. Arch Gen Psychiatry. 1990;47(9):849–853. https://doi.org/10.1001/archpsyc.1990.01810210057008.

10. Zwart JA, Dyb G, Hagen K, Ødegård KJ, Dahl AA, Bovim G, Stovner LJ. Depression and anxiety disorders associated with headache frequency. The Nord-Trøndelag Health Study. Eur J Neurol. 2003;10(2):147–152. https://doi.org/10.1046/j.1468-1331.2003.00551.x.

11. Blumenfeld A, Varon S, Wilcox TK, Buse D, Kawata AK, Manack A et al. Disability, HRQoL and resource use among chronic and episodic migraineurs: results from the International Burden of Migraine Study (IBMS). Cephalalgia. 2011;31(3):301–315. https://doi.org/10.1177/0333102410381145.

12. Chen YC, Tang CH, Ng K, Wang SJ Comorbidity profiles of chronic migraine sufferers in a national database in Taiwan. J Headache Pain. 2012;13(4):311–319. https://doi.org/10.1007/s10194-012-0447-4.

13. Peterlin BL, Tietjen GE, Brandes JL, Rubin SM, Drexler E, Lidicker JR, Meng S. Posttraumatic stress disorder in migraine. Headache. 2009;49(4):541–551. https://doi.org/10.1111/j.1526-4610.2009.01368.x.

14. Kessler RC. Posttraumatic stress disorder: the burden to the individual and to society. J Clin Psychiatry. 2000;61(Suppl. 5):4–12. Available at: https://www.psychiatrist.com/jcp/posttraumatic-stress-disorder-burdenindividual-society/.

15. Peterlin BL, Tietjen G, Meng S, Lidicker J, Bigal M. Posttraumatic stress disorder in episodic and chronic migraine. Headache. 2008;48(4):517–522. https://doi.org/10.1111/j.1526-4610.2008.00917.x.

16. Tietjen GE, Brandes JL, Peterlin BL, Eloff A, Dafer RM, Stein MR et al. Childhood maltreatment and migraine (part II). Emotional abuse as a risk factor for headache chronification. Headache. 2010;50(1):32–41. https://doi.org/10.1111/j.1526-4610.2009.01557.x.

17. Peterlin BL, Rosso AL, Sheftell FD, Libon DJ, Mossey JM, Merikangas KR . Post-traumatic stress disorder, drug abuse and migraine: new findings from the National Comorbidity Survey Replication (NCS-R). Cephalalgia. 2011;31(2):235–244. https://doi.org/10.1177/0333102410378051.

18. Buse DC, Silberstein SD, Manack AN, Papapetropoulos S, Lipton RB. Psychiatric comorbidities of episodic and chronic migraine. J Neurol. 2013;260(8):1960–1969. https://doi.org/10.1007/s00415-012-6725-x.

19. Raudenská J, Macko T, Vodičková Š, Buse DC, Javůrková A. Anxiety Disorders, Anxious Symptomology and Related Behaviors Associated With Migraine: A Narrative Review of Prevalence and Impact. Curr Pain Headache Rep. 2025;29(1):40. https://doi.org/10.1007/s11916-024-01312-9.

20. Dresler T, Caratozzolo S, Guldolf K, Huhn JI, Loiacono C, Niiberg-Pikksööt T et al. Understanding the nature of psychiatric comorbidity in migraine: a systematic review focused on interactions and treatment implications. J Headache Pain. 2019;20(1):51. https://doi.org/10.1186/s10194-019-0988-x.

21. Merikangas KR, Merikangas JR, Angst J. Headache syndromes and psychiatric disorders: association and familial transmission. J Psychiatr Res. 1993;27(2):197–210. https://doi.org/10.1016/0022-3956(93)90008-p.

22. Burstein R, Jakubowski M. Neural substrate of depression during migraine. Neurol Sci. 2009;30(Suppl. 1):S27–S31. https://doi.org/10.1007/s10072-009-0061-7.

23. Hamel E. Serotonin and migraine: biology and clinical implications. Cephalalgia. 2007;27(11):1293–1300. https://doi.org/10.1111/j.1468-2982.2007.01476.x.

24. Smitherman TA, Penzien DB, Maizels M. Anxiety disorders and migraine intractability and progression. Curr Pain Headache Rep. 2008;12(3):224–229. https://doi.org/10.1007/s11916-008-0039-9.

25. Barbanti P, Fabbrini G, Ricci A, Pascali MP, Bronzetti E, Amenta F et al. Migraine patients show an increased density of dopamine D3 and D4 receptors on lymphocytes. Cephalalgia. 2000;20(1):15–19. https://doi.org/10.1046/j.1468-2982.2000.00001.x.

26. Mittinty MM, McNeil DW, Brennan DS, Randall CL, Mittinty MN, Jamieson L. Assessment of pain-related fear in individuals with chronic painful conditions. J Pain Res. 2018;11:3071–3077. https://doi.org/10.2147/JPR.S163751.

27. Chen Z, Chen X, Liu M, Ma L, Yu S. Lower hippocampal subfields volume in relation to anxiety in medication-overuse headache. Mol Pain. 2018;14:1744806918761257. https://doi.org/10.1177/1744806918761257.

28. Zale EL, Lange KL, Fields SA, Ditre JW. The relation between pain-related fear and disability: a meta-analysis. J Pain. 2013;14(10):1019–1030. https://doi.org/10.1016/j.jpain.2013.05.005.

29. Rogers DG, Protti TA, Smitherman TA. Fear, Avoidance, and Disability in Headache Disorders. Curr Pain Headache Rep. 2020;24(7):33. https://doi.org/10.1007/s11916-020-00865-9.

30. Farris SG, Burr EK, Abrantes AM, Thomas JG, Godley FA, Roth JL et al. Anxiety sensitivity as a risk indicator for anxiety, depression, and headache severity in women with migraine. Headache. 2019;59(8):1212–1220. https://doi.org/10.1111/head.13568.

31. Farris SG, Thomas JG, Abrantes AM, Lipton RB, Burr EK, Godley FA et al. Anxiety sensitivity and intentional avoidance of physical activity in women with probable migraine. Cephalalgia. 2019;39(11):1465–1459. https://doi.org/10.1177/0333102419861712.

32. Norton PJ, Asmundson GJ. Anxiety sensitivity, fear, and avoidance behavior in headache pain. Pain. 2004;111(1-2):218–223. https://doi.org/10.1016/j.pain.2004.06.018.

33. Davis RE, Smitherman TA, Baskin SM. Personality traits, personality disorders, and migraine: a review. Neurol Sci. 2013;34(Suppl. 1):S7–S10. https://doi.org/10.1007/s10072-013-1379-8.

34. Balottin U, Fusar Poli P, Termine C, Molteni S, Galli F. Psychopathological symptoms in child and adolescent migraine and tension-type headache: a meta-analysis. Cephalalgia. 2012;33(2):112–122. https://doi.org/10.1177/0333102412468386.

35. Galli F, Caputi M, Sances G, Vegni E, Bottiroli S, Nappi G, Tassorelli C. Alexithymia in chronic and episodic migraine: a comparative study. J Ment Health. 2017;26(3):192–196. https://doi.org/10.3109/09638237.2015.1124404.

36. Swartz KL, Pratt LA, Armenian HK, Lee LC, Eaton WW. Mental disorders and the incidence of migraine headaches in a community sample: results from the Baltimore epidemiologic catchment area follow-up study. Arch Gen Psychiatry. 2000;57(10):945–950. https://doi.org/10.1001/archpsyc.57.10.945.

37. Peres MF, Mercante JP, Guendler VZ, Corchs F, Bernik MA, Zukerman E, Silberstein SD. Cephalalgiaphobia: a possible specific phobia of illness. J Headache Pain. 2007;8(1):56–59. https://doi.org/10.1007/s10194-007-0361-3.

38. Giannini G, Zanigni S, Grimaldi D, Melotti R, Pierangeli G, Cortelli P, Cevoli S. Cephalalgiaphobia as a feature of high-frequency migraine: a pilot study. J Headache Pain. 2013;14(1):49. https://doi.org/10.1186/1129-2377-14-49.

39. Suhr J, Spickard B. Pain-related fear is associated with cognitive task avoidance: exploration of the cogniphobia construct in a recurrent headache sample. Clin Neuropsychol. 2012;26(7):1128–1141. https://doi.org/10.1080/13854046.2012.713121.

40. Tension-type headache. Nat Rev Dis Primers. 2021;7(1):23. https://doi.org/10.1038/s41572-021-00263-4.

41. Pan LH, Ling YH, Wang SJ, Al-Hassany L, Chen WT, Chiang CC et al. Hallmarks of primary headache: part 2 – Tension-type headache. J Headache Pain. 2025;26(1):164. https://doi.org/10.1186/s10194-025-02098-w.

42. de Tommaso M, Fernández-de-Las-Penas C. Tension Type Headache. Curr Reumatol Rev. 2016;12(2):127–139. https://doi.org/10.2174/1573397112666151231113625.

43. Repiso-Guardeño Á, Moreno-Morales N, Labajos-Manzanares MT, Rodríguez-Martínez MC, Armenta-Peinado JA. Does Tension Headache Have a Central or Peripheral Origin? Current State of Affairs. Curr Pain Headache Rep. 2023;27(11):801–810. https://doi.org/10.1007/s11916-023-01179-2.

44. Heckman BD, Holroyd KA. Tension-type headache and psychiatric comorbidity. Curr Pain Headache Rep. 2006;10(6):439–447. https://doi.org/10.1007/s11916-006-0075-2.

45. Spierings EL, Ranke AH, Honkoop PC. Precipitating and aggravating factors of migraine versus tension-type headache. J Head Face Pain. 2001;41(6):554–558. https://doi.org/10.1046/j.1526-4610.2001.041006554.x.

46. Leistad R, Sand T, Westgaard R, Nilsen K, Stovner L. Stress induced pain and muscle activity in patients with migraine and tension-type headache. Cephalalgia. 2006;26(1):64–73. https://doi.org/10.1111/j.1468-2982.2005.00997.x.

47. Guidetti V, Galli F, Fabrizi P, Giannantoni AS, Napoli L, Bruni O, Trillo S. Headache and psychiatric comorbidity: clinical aspects and outcome in an 8-year follow-up study. Cephalalgia. 1998;18(7):455–462. Available at: https://pubmed.ncbi.nlm.nih.gov/9793697/.

48. Puca F, Genco S, Prudenzano MP, Savarese M, Bussone G, D’Amico D et al. Psychiatric comorbidity and psychosocial stress in patients with tensiontype headache from headache centers in Italy. The Italian Collaborative Group for the Study of Psychopathological Factors in Primary Headaches. Cephalalgia. 1999;19(3):159–164. https://doi.org/10.1046/j.1468-2982.1999.1903159.x.

49. Holroyd KA, Stensland M, Lipchik GL, Hill KR, O’Donnell FS, Cordingley G. Psychosocial correlates and impact of chronic tension-type headaches. Headache. 2000;40(1):3–16. https://doi.org/10.1046/j.1526-4610.2000.00001.x.

50. Mongini F, Ciccone G, Deregibus A, Ferrero L, Mongini T. Muscle tenderness in different headache types and its relation to anxiety and depression. Pain. 2004;112(1-2):59–64. https://doi.org/10.1016/j.pain.2004.07.025.

51. Giri S, Tronvik EA, Hagen K. The bidirectional temporal relationship between headache and affective disorders: longitudinal data from the HUNT studies. J Headache Pain. 2022;23(1):14. https://doi.org/10.1186/s10194-022-01388-x.

52. Ghogare AS, Patil PS. A cross-sectional study of co-morbid generalized anxiety disorder and major depressive disorder in patients with tensiontype headache attending tertiary health care centre in central rural India. Nigerian Postgrad Med J. 2020;27(3):224–229. https://doi.org/10.4103/npmj.npmj_23_20.

53. Juang KD, Wang SJ, Fuh JL, Lu SR, Su TP. Comorbidity of depressive and anxiety disorders in chronic daily headache and its subtypes. Headache. 2000;40(10):818–823. https://doi.org/10.1111/j.1526-4610.2000.00148.x.

54. Romero-Godoy R, Romero-Godoy SR, Romero-Acebal M, Gutiérrez-Bedmar M. Psychiatric comorbidity and emotional dysregulation in chronic TensionType headache: A Case-Control study. J Clin Med. 2022;11(17):5090. https://doi.org/10.3390/jcm11175090.

55. Hu T, Zhang D, Wang J, Mistry R, Ran G, Wang X. Relation between emotion regulation and mental health: A meta-analysis review. Psychol. Rep. 2014;114(2):341–362. https://doi.org/10.2466/03.20.PR0.114k22w4.

56. Haratian A, Amjadi MM, Ghandehari K, Hatamian H, Kiani S, Habibi M et al. Emotion Regulation Difficulties and Repetitive Negative Thinking in Patients with Tension Headaches and Migraine. Casp J Neurol Sci. 2020;6(3):147–155. https://doi.org/10.32598/CJNS.6.22.3.

57. Nauser JW, Nelson CI, Gross RT, Vargovich AM. Pain Experiences and Their Relation to Opioid Misuse Risk and Emotion Dysregulation. Pain Res Manag. 2020;2020:7234625. https://doi.org/10.1155/2020/7234625.

58. Steel SJ, Robertson CE, Whealy MA. Current Understanding of the Pathophysiology and Approach to Tension-Type Headache. Curr Neurol Neurosci Rep. 2021;21(10):56. https://doi.org/10.1007/s11910-021-01138-7.

59. Fuensalida-Novo S, Palacios-Ceña M, Fernández-Muñoz JJ, Castaldo M, Wang K, Catena A et al. The burden of headache is associated to pain interference, depression and headache duration in chronic tension type headache: a 1-year longitudinal study. J Headache Pain. 2017;18(1):119. https://doi.org/10.1186/s10194-017-0829-8.

60. Smitherman TA, Baskin SM. Headache secondary to psychiatric disorders. Curr Pain Headache Rep. 2008;12(4):305–310. https://doi.org/10.1007/s11916-008-0051-0.

61. Ashina S, Bendtsen L, Buse D, Lyngberg A, Lipton R, Jensen R. Neuroticism, depression and pain perception in migraine and tension-type headache. Acta Neurol Scand. 2017;136(5):470–476. https://doi.org/10.1111/ane.12751.

62. Accogli G, Nicolardi V, Ferrante C, Carlucci G, Scoditti S, Trabacca A. Beyond the Pain: A Critical Examination of the Psychopathological and Neuropsychological Dimensions of Primary Headaches in Pediatric Populations. Life. 2025;15(10):1641. https://doi.org/10.3390/life15101641.

63. D’Andrea G, Hasselmark L, Cananzi A, Alecci M, Perini F, Zamberlan F, Welch KM. Metabolism and menstrual cycle rhythmicity of serotonin in primary headaches. Headache. 1995;35(4):216–221. https://doi.org/10.1111/j.1526-4610.1995.hed3504216.x.

64. Bendtsen L. Central sensitization in tension-type headache – possible pathophysiological mechanisms. Cephalalgia. 2000;20(5):486–508. https://doi.org/10.1046/j.1468-2982.2000.00070.x.

65. Chen WT, Chou KH, Lee PL, Hsiao FJ, Niddam DM, Lai KL et al. Comparison of gray matter volume between migraine and “strict-criteria” tension-type headache. J Headache Pain. 2018;19(1):4. https://doi.org/10.1186/s10194-018-0834-6.

66. Schmidt-Wilcke T, Leinisch E, Straube A, Kampfe N, Draganski B, Diener HC et al. Gray matter decrease in patients with chronic tension type headache. Neurology. 2005;65(9):1483–1486. https://doi.org/10.1212/01.wnl.0000183067.94400.80.

67. Rasmussen BK. Migraine and tension-type headache in a general population: precipitating factors, female hormones, sleep pattern and relation to lifestyle. Pain. 1993;53(1):65–72. https://doi.org/10.1016/0304-3959(93)90057-V.

68. Cathcart S, Winefield AH, Lushington K, Rolan P. Stress and tension-type headache mechanisms. Cephalalgia. 2010;30(10):1250–1267. https://doi.org/10.1177/0333102410362927.

69. Choi J, Chung M, Lee Y. Modulation of pain sensation by stress-related testosterone and cortisol. Anaesthesia. 2012;67(10):1146–1151. https://doi.org/10.1111/j.1365-2044.2012.07267.x.

70. Sousa-Santos PEM, Peres MFP. Practical issues in the management of sleep, anxiety, and mood disorders in primary headaches. Arq Neuropsiquiatr. 2025;83(7):s00451809881. https://doi.org/10.1055/s-0045-1809881.

71. Lipton RB, Fanning KM, Buse DC, Martin VT, Reed ML, Adams AM, Goadsby PJ. Identifying Natural Subgroups of Migraine Based on Comorbidity and Concomitant Condition Profiles: Results of the Chronic Migraine Epidemiology and Outcomes (CaMEO) Study. Headache. 2018;58(7):933–947. https://doi.org/10.1111/head.13342.

72. Tabeeva GR, Artemenko AR, Koreshkina MI, Osipova VV, Sergeev AV, Latysheva NV et al. Overcoming obstacles to effective treatment of patients with migraine (Statement of the expert group on optimizing treatment of patients with migraine). Neurology, Neuropsychiatry, Psychosomatics. 2025;17(2):4–14. (In Russ.) https://doi.org/10.14412/2074-2711-2025-2-4-14.

73. Guziy EA, Sergeev AV, Tabeeva GR. Evaluation of the efficacy of preventive therapy in chronic migraine with or without medication overuse headache: data from a prospective study. Neurology, Neuropsychiatry, Psychosomatics. 2024;16(1S):59–65. (In Russ.) https://doi.org/10.14412/2074-2711-2024-1S-59-65.

74. Tabeeva GR, Kosivtsova OV, Kovalchuk NA, Orlyuk TA. Refractory migraine. Neurology, Neuropsychiatry, Psychosomatics. 2024;16(2):76–86. (In Russ.) https://doi.org/10.14412/2074-2711-2024-2-76-86.

75. Guziy EA, Sergeev AV, Tabeeva GR. Analyzing the predictors of relapse in drug-induced headache: a prospective clinical and psychological study. Neurology, Neuropsychiatry, Psychosomatics. 2024;16(3):44–51. (In Russ.) https://doi.org/10.14412/2074-2711-2024-3-44-51.

76. Tabeeva GR, Filatova EG, Amelin AV, Osipova VV, Artemenko AR, Akhmadeeva LR et al. Alternative and complementary treatments for migraine. Neurology, Neuropsychiatry, Psychosomatics. 2024;16(1):4–15. (In Russ.) https://doi.org/10.14412/2074-2711-2024-1-4-15.

77. Tabeeva GR, Amelin AV, Vaganova YS, Kovalchuk NA, Trinitatskiy YV, Khaibullina DK et al. Tension-type headache and effective pain relief: results of the prospective multicenter RAPID clinical trial. Neurology, Neuropsychiatry, Psychosomatics. 2025;17(3):49–59. (In Russ.) https://doi.org/10.14412/2074-2711-2025-3-49-59.

78. Asmundson GJ, Katz J. Understanding the co-occurrence of anxiety disorders and chronic pain: state-of-the-art. Depress Anxiety. 2009;26(10):888–901. https://doi.org/10.1002/da.20600.

79. Hamon A, Morel A, Hue B, Verleye M, Gillardin JM. The modulatory effects of the anxiolytic etifoxine on GABA(A) receptors are mediated by the beta subunit. Neuropharmacology. 2003;45(3):293–303. https://doi.org/10.1016/s0028-3908(03)00187-4.

80. Schlichter R, Rybalchenko V, Poisbeau P, Verleye M, Gillardin J. Modulation of GABAergic synaptic transmission by the non-benzodiazepine anxiolytic etifoxine. Neuropharmacology. 2000;39(9):1523–1535. https://doi.org/10.1016/s0028-3908(99)00253-1.

81. Aouad M, Charlet A, Rodeau JL, Poisbeau P. Reduction and prevention of vincristine-induced neuropathic pain symptoms by the non-benzodiazepine anxiolytic etifoxine are mediated by 3alpha-reduced neurosteroids. Pain. 2009;147(1-3):54–59. https://doi.org/10.1016/j.pain.2009.08.001.

82. Aouad M, Zell V, Juif PE, Lacaud A, Goumon Y, Darbon P et al. Etifoxine analgesia in experimental monoarthritis: a combined action that protects spinal inhibition and limits central inflammatory processes. Pain. 2014;155:403–412. https://doi.org/10.1016/j.pain.2013.11.003.

83. Nuss P, Ferreri F, Bourin M. An update on the anxiolytic and neuroprotective properties of etifoxine: from brain GABA modulation to a whole-body mode of action. Neuropsychiatr Dis Treat. 2019;15:1781–1795. https://doi.org/10.2147/NDT.S200568.