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Y.E. Azimova

Scientific Research Institute of General Pathology and Pathophysiology;
University Headache Clinic

K.V. Skorobogatykh

«University Headache Clinic» LLC

V.V. Osipova

M.L. Kukushkin

Research Institute of General Pathology and Pathophysiology

D.Z. Korobkova

University Headache Clinic LLC

N.V. Vashchenko

University Headache Clinic LLC;
Sechenov First Moscow State Medical University

A.M. Uzhakhov

University Headache Clinic LLC;
Research Institute of General Pathology and Pathophysiology

S.Yu. Kornienko

University Headache Clinic LLC

E.Z. Mamkhegov

University Headache Clinic LLC

Influence of significant stressful events on the course of primary cephalalgia


Y.E. Azimova, K.V. Skorobogatykh, V.V. Osipova, M.L. Kukushkin, D.Z. Korobkova, N.V. Vashchenko, A.M. Uzhakhov, S.Yu. Kornienko, E.Z. Mamkhegov

More about the authors

Journal: Russian Journal of Pain. 2023;21(1): 26‑32

Views: 1471

Downloaded: 75

To cite this article:

Azimova YE, Skorobogatykh KV, Osipova VV, Kukushkin ML, Korobkova DZ, Vashchenko NV, Uzhakhov AM, Kornienko SYu, Mamkhegov EZ. Influence of significant stressful events on the course of primary cephalalgia. Russian Journal of Pain. 2023;21(1):26‑32. (In Russ., In Engl.)

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The University Headache Clinic is a specialized center providing care to patients with cephalalgia according to national and international evidence-based guidelines [1, 3, 6, 20, 21]. Headache is diagnosed in accordance with the diagnostic criteria of the International Classification of Headache Disorders (third edition, ICHD-3) (2018) [18] and ICD-10 criteria. Clinical interview is associated with behavioral therapy. We explain to the patient the mechanisms of headache, the need to avoid triggers and risk factors of chronic cephalalgia, as well as lifestyle modification. The patient is also explained the essence of disease and therapeutic possibilities. The physician and the patient choose treatment strategy together considering the form of headache and comorbidities.

A stressful event is the most common trigger of migraine attack [22]. Along with depression and drug abuse, stress is a leading factor of chronic transformation of primary cephalalgia (migraine and tension-type headache (TTH)) [22]. Many patients experience emotional stress. The most common stressful events are family problems, conflicts at work, illness of the patient or relatives, financial difficulties, litigation, etc.

In the last 2 years, significant stressful events related to the novel coronavirus infection (COVID-19) pandemic, special military operation and their socio-economic consequences have been added to this list. Obviously, these events can adversely affect the patients suffering from headache.

For example, Buse D.C. et al. [10] conducted a structured interview of patients with migraine about the impact of the COVID-19 pandemic on the course of their disease. Patients reported both positive and negative effects. The positive factor was remote work from home that is more comfortable for many people, especially in case of migraine. The negative factors included anxiety, isolation (impossibility of free movement and habitual communication), and unavailability of medical care. Another large American study enrolling 163,176 migraine patients revealed that migraine attacks were caused by stress factors such as social isolation (22.6%), negative information background (21.2%), no access to familiar products and drugs (18.7%), financial difficulties (17.8%) [16]. Spanish researchers revealed deterioration of migraine during lockdown in 47% of patients and improvement in only 14% of patients [14]. In summary, the COVID-19 pandemic and pandemic-related stressors have negatively impacted people with migraine across countries. There is no a similar analysis of the impact of the pandemic on the course of tension-type headache.

Another stress factor can be socio-economic upheavals associated, among other things, with sanctions and isolation. The influence of socioeconomic factors on headache has been well studied in Iran. The prevalence of migraine in this state is 14%, in Tehran — 27.6% [19]. These values are higher than in the countries of the European Union, Latin America, in the USA, but close to the prevalence of migraine in the Russian Federation and India. Significant stressors for patients with migraine are racial and economic inequality, climate (high mountains), peculiarities of national cuisine and social factors [12]. The highest incidence of chronic headache was noted in the Mazandaran province (13% of population). The factors associated with chronic headache were female gender, living in highlands, previous head trauma and depression [5].

The purpose of this study was to analyze diagnoses, clinical characteristics, incidence and specifics of comorbid mental and other disorders in Russian patients with a main complaint of headache before and after the novel coronavirus infection (COVID-19) pandemic and special military operation.

Material and methods

We retrospectively analyzed primary medical records of all patients over 16 years old with headache between April 1, 2019 and July 1, 2019 (before the COVID-19 pandemic), in 2021 (during the COVID-19 pandemic) and 2022 (after onset of special military operation). Seven specialists for headache followed-up the patients and electronic database. The forms of headache and comorbid mental disorders were diagnosed according to the criteria of ICHD-3 (2018) and ICD-10.

According to standards of record keeping in the hospital, the number of days with one or another type of cephalalgia is also recorded in the medical record along with diagnosis of headache per se. Moreover, all patients were examined for anxiety and/or depressive disorders.

We recorded the symptoms of depression, such as low mood, anhedonia, anergia (no internal energy), sleep disturbances, etc.

Neurological and somatic comorbidities were also taken into account. We considered therapy for relief of attacks and prevention of migraine, as well as treatment of comorbid disorders, including antidepressants, if they were prescribed for the treatment of depression and anxiety rather prevention of migraine.

Statistical analysis was performed using the SPSS 10.0 software package. We used descriptive characteristics to analyze frequencies and means. All indicators were tested for normal distribution using the Kolmogorov–Smirnov test. In case of normal distribution, parametric methods were used. Chi-square test was used to compare percentages between groups. In case of abnormal distribution, non-parametric methods were used (Wilcoxon-Mann-Whitney U-test). Differences were significant at p-value<0.05.


Description of population

The overall structure of diagnoses in 2019, 2021 and 2022 is presented in Table 1. The vast majority of patients had one form of headache. Only one patient had two forms (episodic migraine and chronic TTH).

Table 1. Diagnoses in patients with headache in 2019, 2021 and 2022


% (n)


83.2% (706)

Drug-induced headache

22.9% (94)

Tension-type headache (any form)

12.7% (108)

Chronic tension-type headache

7.2% (61)

Episodic tension-type headache

5.5% (47)

Temporomandibular joint dysfunction

3.5% (30)

Cluster headache

2.2% (19)

Hemicrania continua

0.9% (8)

Cervicogenic headache

0.8% (7)

Atypical facial pain

0.2% (2)

Headache associated with head and neck tumor

0.2% (2)

Vertebral artery dissection

0.2% (2)

Benign intracranial hypertension

0.2% (2)

Intracranial hypotension

0.2% (2)

Hypnic headache

0.2% (2)

Other forms of headache: SUNA, primary cough, coital, lactational, hypertension- and subdural hematoma-associated headache, trigeminal neuralgia

by 0.1% (1)

Thus, migraine was the most common diagnosis. Drug-induced headache was at the second place, TTH — at the third place. Secondary headaches, especially potentially life-threatening ones, were rare. These findings are in line with data from other headache centers in the world.

Characteristics of patients with migraine

There were 601 (85.1%) women and 104 (14%) men with migraine. Mean age of patients was 37.4±17.9 years (range 16-76). The majority of patients had episodic migraine (58.6%, n=292). Chronic migraine was diagnosed in 41.4% of patients (n=414). In 26.6% (n=188) of patients, migraine was combined with drug-induced headache. Migraine with aura was observed in 106 (15%) patients. Migraine resistant to ≥ 2 classes of adequate antimigraine agents was observed in 64 (9.1%) patients. Hospital-stay in patients with headache and migraine was 14.6±9.7 and 13.4±9.4 days, respectively.

Comorbid emotional-affective and other mental disorders were common in patients with migraine. Anxiety was detected in 38.8% (n=274) of patients, depression — n 35.8% (n=253), panic attacks —5.4% (n=38), somatoform disorder — 3.3% (n=23) of patients.

Somatic comorbidities were found in 38.7% (n=273) of patients. The most common were arterial hypertension, myofascial syndromes, bruxism, autoimmune thyroiditis and iron deficiency anemia.

All patients were given advice on stopping attacks. We performed behavioral therapy including conversation about the role of drug abuse in chronic migraine and the need for treatment/prevention of drug-induced headache. The majority of patients (83%, n=586) had indications for preventive therapy. Anti-CGRP-monoclonal antibodies were recommended in more than a third of patients: fremanezumab — 21.7% (n=154), erenumab — 13.7% (n=97), beta-blockers (propranolol or metoprolol) — 14.1% (n=101), candesartan — 8.9% (n=66), amitriptyline — 8.2% (n=58), topiramate — 5.6% (n=40) of patients. Other drugs and prevention methods were less common (botulinum toxin, venlafaxine, calcium channel blockers, non-invasive neurostimulation using the Cefaly device). Antidepressants were recommended in more than a third of patients (32.4%, 229 people) for depression and anxiety.

Characteristics of patients with chronic tension-type headache

TTH was diagnosed in 108 (12.7%) patients including 7.2% with chronic TTH. There were 21 (31.4%) men and 40 (65.6%) women aged 42.3±14.1 years. Hospital-stay in patients with headache was 25.7±6.7 days per a month that indicated severe course of chronic TTH. Depression was diagnosed in 65.6% (n=40) of patients, anxiety — 63.3% (n=38), somatoform disorder — 21.3% (n=13), panic attacks –14.8% (n=9) of patients. Chronic pain syndromes of other localizations were noted in 16.4% (n=10) of patients, comorbid somatic and/or neurological diseases — in 52.5% (n=32) of patients.

Drug prophylaxis was prescribed in 72.4% (n=42) of patients. Amitriptyline was the most common, venlafaxine and clomipramine — less common drugs. Non-drug methods (psychotherapy, relaxation training, physical activity) were recommended in other patients. Antidepressants for depression were prescribed in 65.6% (n=40) of patients.

Characteristics of patients in 2019, 2021 and 2022

Characteristics of patients in 2019, 2021 and 2022 are presented in Table 2. The number of patients with headache has progressively increased over 3 years. Women prevailed, but mean age of patients decreased.

Table 2. Characteristics of patients in different years







Number of patients with headache




Men, n (%)

36 (23.5%)

58 (21.9%)


72 (16.7%)


Women, n (%)

117 (76.5)

207 (28.1)


360 (83.3)


Mean age, years







Number of patients with migraine, n (%)

115 (72.5%)

223 (84.2%)


368 (85.2%)


Anamnesis of migraine, years






Number of patients with migraine and aura among patients with migraine, n (%)

12 (10.4%)

26 (11.7%)


68 (18.5%)


Number of patients with episodic migraine among patients with migraine, n (%)

69 (60.0%)

130 (58.3%)


215 (58.4%)


Number of patients with chronic migraine among patients with migraine, n (%)

46 (40.0%)

93 (41.7%)


152 (41.3%)


Number of patients with resistance to ≥ 2 classes of anti-migraine agents for migraine prophylaxis among patients with migraine, n (%)

9 (7.8%)

18 (8.1%)


37 (10.1%)


Number of days with headache per a month






Number of days with migraine per a month






Number of patients with drug-induced headache, n (%)

35 (22.9%)

66 (24.9%)


93 (21.5%)


Number of patients with preventive therapy for migraine, n (%)

88 (65.1%)

200 (80.6%)


325 (81.3%)


Tension-type headache

Number of patients with episodic tension-type headache, n (%)

8 (5.2%)

17 (6.4%)


23 (5.3%)


Number of patients with chronic tension-type headache, n (%)

14 (9.2%)

20 (7.5%)


27 (6.3%)


Number of days with headache per a month






Comorbid disorders

Number of patients with depression, n (%)

49 (32%)

76 (28.7%)


188 (43.9%)


Anamnesis of depression, years






Number of patients with depression de novo, n (%)

4 (2.6%)

7 (2.7%)


31 (21.3%)


Patients with a specified symptom among all patients with depression

Number of patients with significant mood impairment among patients with depression, n (%)

34 (69.4%)

48 (75.0%)


116 (76.3%)


Number of patients with anhedonia among patients with depression, n (%)

35 (71.4%)

62 (96.9%)


130 (85.5%)


Number of patients with pessimism among patients with depression, n (%)

13 (21.7%)

26 (40.6%)


62 (41.1%)


Number of patients with sleep disorders among patients with depression, n (%)

44 (89.8%)

48 (75.0%)


130 (85.5%)


Number of patients with anergia among patients with depression, n (%)

39 (79.6%)

61 (95.3%)


131 (86.2%)


Number of patients with feelings of guilt among patients with depression, n (%)

13 (8.5%)

14 (21.9%)


53 (34.6)


Number of patients with impaired attention among patients with depression, n (%)

31 (63.3%)

28 (43.8%)


61 (40.1%)


Number of patients with suicidal thoughts among patients with depression, n (%)

5 (10.2%)

6 (9.3%)


10 (6.5%)


Number of patients with a specified symptom or therapy among all patients

Number of patients with anxiety, n (%)

24 (28.8%)

119 (44.9%)


179 (43.6%)


Number of patients with possible somatoform disorder, n (%)

12 (7.8%)

19 (7.2%)


25 (6.1%)


Number of patients prescribed an antidepressant, n (%)

50 (32.7%)

92 (34.7%)


143 (33.5%)


Number of patients with chronic pain of other localization, n (%)

10 (6.5%)

12 (4.5%)


34 (8.3%)


Number of patients referred to the psychiatrist, n (%)

3 (2%)

64 (7.5%)


44 (10.2%)


We noted more visits of patients diagnosed with migraine in 2021. In April-June 2022, percentage of patients with migraine and aura significantly increased from 11.7 to 18.5% (p=0.03). The number of patients prescribed prophylactic therapy also increased in 2021. Perhaps, this is due to request for a new targeted migraine therapy. Other migraine characteristics remained the same over 3 years.

Emotional background changed significantly in 2021 and 2022 compared to 2019 (Table 2). Thus, the number of patients with anxiety increased from 28.0 (24 people) to 44.9% (119 people) in 2021 (p=0.001). Anxiety was still high in 2022. The prevalence of depression did not change significantly in 2021 compared to 2019, but its manifestations changed. Anhedonia and anergia became more common (Table 2). In 2021, the number of patients referred to the psychiatrist increased from 2 to 7.5% (p=0.001). The number of patients with depression significantly increased among patients with headache from 28.7% (n=76) in 2021 to 43.9% (n=188) in 2022 (p=0.0001). The number of patients with a first-time depressive episode significantly increased from 2.7% in 2021 to 21.3% in 2022 (p=0.0001). The number of patients referred to the psychiatrist was 10.2% in 2022 that was significantly higher compared to 2021.

Importantly, the number of patients with chronic pain of other localization (chronic non-specific musculoskeletal pain, fibromyalgia, pelvic pain, etc.) significantly increased in 2022 compared to 2019 and 2021 (8.3%) (Table 2).


We retrospectively analyzed primary medical records of patients with headache who referred to the specialized headache clinic for 3 years: before the COVID-19 pandemic — between April and June 2019, during the COVID-19 pandemic — between April and June 2021, after onset of special military operation — between April and June 2022. The vast majority of patients had primary headache (migraine and TTH). We revealed certain features in the course of migraine and TTH, as well as mental comorbid disorders following stress factors.

The number of patients with headache has progressively increased over the past 3 years. Moreover, mean age of these patients decreased.

The number of patients prescribed prophylactic therapy also increased in 2021 that may be due to demand for new methods of targeted migraine therapy.

The number of patients with migraine and aura significantly increased in April-June 2022. Some other authors found the same trend [17]. Winter A.C. et al. [27] observed the negative impact of socioeconomic stress on the course of all types of headache, especially migraine with aura. There is a relationship between the aura and post-traumatic stress disorder. Hinton D.E. et al. [15] analyzed 150 Cambodian refugees who survived long and cruel hostilities. Along with post-traumatic stress disorder, 36% of patients developed migraine with visual aura for the first time. Theeler B.J. et al. [26] found higher prevalence of migraine among US military personnel compared to general population (19%). Stress combined with sleep disturbance during military exercises was the most significant trigger.

Stubberud A. et al. [25] analyzed the relationship between stress and risk of migraine attack. On the one hand, stress exposure through activation of hypothalamic-pituitary-adrenal axis can provoke migraine attack. On the other hand, functional cerebral disorders (in particular, activation of hypothalamus) in prodromal phase of migraine can reduce stress resistance. Finally, the patient can perceive trivial troubles as excessive factors leading to migraine attack. The possible mechanism of migraine aura under stress is interesting. Experimental studies revealed that serum cortisol elevated under stress increases neuronal excitability and lowers the threshold for cortical depression. The last phenomenon underlies migraine aura [24].

Several studies identified significant impact of the COVID-19 pandemic as a stress factor on emotional background of patients, i.e. prevalence and clinical features of anxiety and depression. In a population-based Italian study conducted in 2020, the prevalence of anxiety increased from 21.4 to 35.7% and depression from 15.4 to 32.3% [13]. Analysis of 1040 people from 5 countries revealed depression in 53% of people during the COVID-19 pandemic and post-traumatic stress disorder in 13% of people [8]. Another study of 85 patients with post-traumatic stress disorder, depression or somatoform disorders revealed emotional numbness and anhedonia as the key symptoms of depressive syndrome during the COVID-19 pandemic [23].

According to our data, the number of patients with depression de novo significantly increased in 2022 due to stressful impacts associated with the COVID-19 pandemic. Stressful events in 2020-2022 could include isolation, limited communication, financial difficulties, job loss, loss of loved ones, unclear prospects, etc. A recent meta-analysis was aimed at identifying associations between major socially significant events and depressive episodes. Deterioration of ≥ 3 socially significant events was a predictor of drug-resistant depression [9].

We found no significant influence of stressful life events in 2020-2022 on the course of primary cephalgia. There was no increase in the number of patients with chronic forms of migraine, TTH and drug-induced headache. Perhaps, this follow-up period is insufficient for clear changes in clinical picture of migraine and TTH. At the same time, it is believed that maladaptive reactions to stressful influences are the most important cause of chronic pain. Zeng F. et al. [28] revealed stressful events as triggers of chronic pain in humans. Excessive and prolonged stress exposure leads to breakdown of innate mechanisms of nonspecific adaptation to stress and emergence of pathological conditions, including depression and chronic pain. The relationship between emotional stress and severity of pain may be due to certain factors such as increased excitability of neurons of central nociceptive and autonomic nervous systems and muscle tension. Thus, 40% of patients with chronic pain after previous distress have emotional changes. Psychosocial stress may be one of the causative factors of musculoskeletal back pain, and many movement disorders are initiated by both physical causes and emotional stress [2].


Significant socio-economic events can be triggers for onset or relapse of comorbid anxiety-depressive disorders in patients with primary cephalalgia. Moreover, depressive and anxiety syndromes are more severe in patients with migraine and TTH under prolonged social stress that determines the need for examination by psychiatrist or psychotherapist.

Funding. The study had no sponsorship.

The authors declare no conflicts of interest.

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