Clinical effect of flunarizine combined with duloxetine in the treatment of chronic migraine comorbidity of depression and anxiety disorder

Abstract Background Migraine is common in primary headaches, and with the development of social economy and the increase in living pressure, the prevalence of migraine has an upward trend. Objective To observe the clinical effect of flunarizine combined with duloxetine in the treatment of chronic migraine with comorbid depression and anxiety disorders and to provide a reference for clinical treatment. Methods A total of 118 patients with chronic migraine complicated with depression and anxiety disorder admitted to our hospital from June 2018 to August 2020 were selected and divided into two groups according to treatment methods, 59 cases in each group. The control group was treated with flunarizine combined with loxoprofen sodium, and the observation group was treated with flunarizine combined with duloxetine. The changes of electroneurophysiological indexes, tumor necrosis factor‐α (TNF‐α), interleukin‐6 (IL‐6), high sensitivity‐C reactive protein (hs‐CRP), Hamilton depression scale (HAMD) score, and Hamilton anxiety scale (HAMA) score before and after treatment in the two groups were recorded, and the total effective rate of clinical treatment in the two groups was counted. Results After treatment, TNF‐α, IL‐6, and hs‐CRP in the two groups decreased gradually (p < .05). Further comparison between groups showed that TNF‐α, IL‐6, and hs‐CRP in the observation group were lower than those in the control group (p < .05). After treatment, the HAMD score and the HAMA score of the two groups decreased gradually (p < .05). Further comparison between the two groups showed that HAMD score and HAMA score of the observation group were lower than those of the control group (p < .05). Conclusion Flunarizine combined with duloxetine in the treatment of chronic migraine with depression and anxiety disorder can effectively improve neuroelectrophysiological indexes, reduce inflammation, and reduce depression and anxiety.


INTRODUCTION
Chronic migraine is a common type of primary headache in clinic, with recurrent moderate to severe head pain on one or both sides as the main symptom, which is often accompanied by autonomic nervous symptoms such as nausea, vomiting, and phobia. Improper diet, sound and light stimulation, overwork, and negative emotions can cause or aggravate headache. Chronic migraine is associated with anxiety and depression (Bhering Martins et al., 2020). Physical therapy and drug therapy are common methods of clinical treatment of this disease. Flunarizine is the calcium antagonist of piperidine difluoride derivative, which has a certain therapeutic effect on epilepsy and migraine. But it cannot reduce negative emotions and is not conducive to the control of the disease (Peres et al., 2019;Wang et al., 2022).
Duloxetine is a selective serotonin and norepinephrine reuptake inhibitor, which is often used in the treatment of severe depression, diabetic peripheral neuralgia, and female stress urinary incontinence (Gonzalez-Martinez et al., 2020). Studies have found that duloxetine hydrochloride enteric-coated capsules can effectively relieve anxiety and depression, reduce the frequency of migraine attacks and pain, and improve the quality of life of patients (Liu et al., 2021;Peres et al., 2019). However, there are few studies on its effects on neuroelectrophysiological indexes and inflammatory indexes. This study observed the clinical effect of flunarizine combined with duloxetine in the treatment of chronic migraine with depression and anxiety disorder, and provided a reference for clinical treatment.  (Eigenbrodt et al., 2021).

General information
(2) Depression and anxiety disorders meet the diagnostic criteria in the "Chinese Classification and Diagnostic Criteria for Mental Disorders (CCMD-3)" (Chen, 2002). Allergic constitution.

Methods
The control group was treated with flunarizine hydrochloride cap-

Observation indicators and detection methods
The changes of neuroelectrophysiological indexes, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), high-sensitivity C-reactive protein (hs-CRP), HAMD score, and HAMA score before and after treatment in the two groups were recorded, and the total effective rate of clinical treatment in the two groups was counted.
HAMD score and HAMA score: depression and anxiety of patients were evaluated. The higher the score, the heavier the negative emotion. HAMD score < 8 points means no depression; ≥8 points means possible depression; ≥20 points means definitely depression; ≥35 points means severe depression. HAMA score < 7 points means no anxiety; ≥7 points means possible anxiety; ≥14 points means definitely anxiety; ≥ 21 points means obvious anxiety; ≥ 29 points means severe anxiety (Thompson, 2015).
The auditory oddball task was performed before and after 8 weeks of treatment. The standard stimulation was 1000 Hz, 90 dB and the duration was 160 ms. Target stimulation: 1800 Hz, 90 dB, and duration: 160 ms. The amplitude and latency of N2, P3a, and P3b were recorded.
Before treatment and 8 weeks after treatment, 3 ml fasting venous blood was extracted from patients and centrifuged at 4000 r/min for 10 min. Serum levels of TNF-α, IL-6, and hs-CRP were detected by enzyme-linked immunosorbent assay. Detection instrument: Hyperion MR III enzyme labeled instrument, kit for Nanjing Jiancheng Institute of Bioengineering products.

Efficacy criteria
Clinical efficacy criteria: (1) Recovery: after treatment, the clinical symptoms of migraine disappeared, imaging (Transcranial Doppler) showed normal or basically normal.
(2) Significantly effective: after treatment, the clinical symptoms of migraine were significantly reduced compared with those before treatment, the frequency was reduced by ≥ 90%, and imaging showed significant improvement. (3) Effective: after treatment, the clinical symptoms of migraine were alleviated compared with those before treatment, and the frequency of 50% ≤ attack was reduced by < 90%, and the imaging findings were improved. (4) Invalid: did not meet the above standards. Total effective rate = cure rate + significant efficiency + effective rate.

Statistical methods
SPSS19.0 was used to process the data. The measurement index was described by (ŕχ ± s). The t test was used for the comparative analysis of the data. The number of cases was used for the enumeration data.
The Chi-square test was used for the comparative analysis of the data.
p < .05 indicated that the difference was significant.

Comparison of curative effect between the two groups of patients
The total effective rate of the observation group (91.53%) was higher than that of the control group (77.97%), and the difference was significant (p < .05) (see Table 1).

Comparison of neurophysiological indicators between the two groups of patients
The two groups were compared before treatment, and the differences were not significant (p > .05). After treatment, the amplitudes of N2, P3a, and P3b in the two groups increased gradually (p < .05), and the latency of N2, P3a, and P3b decreased gradually (p < .05). Further com-parison between the two groups showed that the amplitudes of N2 (Table 2), P3a (Table 3), and P3b (Table 4) in the observation group were higher than those in the control group (p < .05). The incubation periods of N2 and P3a were lower than those the control group (p < .05), but the latency of P3b was not significantly different from that of the control group (p > .05) (see Table 2).

3.3
Comparison of TNF-α, IL-6, and hs-CRP levels between the two groups The two groups were compared before treatment, and the difference was not significant (p > .05). After treatment, TNF-α, IL-6, and hs-CRP in the two groups decreased gradually (p < .05). Further comparison between the two groups showed that TNF-α, IL-6, and hs-CRP in the observation group were lower than those in the control group (see Table 5).

3.4
Comparison of HAMD score and HAMA score between the two groups The two groups were compared before treatment, and the difference was not significant (p > .05). After treatment, the HAMD score and HAMA score of the two groups decreased gradually (p < .05). Further comparison between the two groups showed that the HAMD score and HAMA score of the observation group were lower than those of the control group (p < .05) (see Table 6).

DISCUSSION
Migraine is a type of abnormal vascular function disease of the head and face caused by dysregulation of the nerve. It occurs for the first time in childhood and adolescence and reaches its peak in middle age and young people. It often has genetic background, which can seriously affect the study and life of patients (Gupta et al., 2008). At present, the pathogenesis of migraine is not fully understood. Previous studies have shown that it is closely related to increased brain excitability, abnor- Flunarizine is a vasodilator that selectively blocks calcium and voltagedependent sodium channels to relieve pain and reduce the number of episodes of periodic pain (Pozo-Rosich & Torres-Ferrus, 2020). Loxoprofen sodium is a nonsteroidal anti-inflammatory drug widely used in the treatment of rheumatoid arthritis, low back and leg pain, neck shoulder wrist syndrome, migraine, and other painful diseases (Lisicki & Schoenen, 2020).
Because anxiety and depression can promote migraine, it is necessary to relieve negative emotions in the treatment of chronic migraine Note: Compared with before treatment,*p < .05. Note: Compared with before treatment,*p < .05.

Number of cases
with depression and anxiety disorder (Cayir et al., 2020). Duloxetine has dual effects of antidepression and central analgesia and has good effect on negative emotions such as anxiety and depression and their induced somatic complications (Kim et al., 2019). This study found that the total effective rate of flunarizine combined with duloxetine was higher than that of flunarizine combined with loxoprofen sodium.
After treatment, the HAMD and HAMA scores were lower than those treated with flavors combined with loopholes sodium. The results suggest that flunarizine combined with duloxetine in the treatment of chronic migraine with depression and anxiety disorder comorbidity can better control migraine attacks and reduce depression and anxiety. This is consistent with the existing clinical findings (Aljunaid et al., 2020). This is because the decrease in serotonin, norepinephrine, and other neurotransmitter levels is closely related to pain and emotional disorders. Duloxetine has a high affinity to 5-hydroxytryptamine and norepinephrine receptors, and can inhibit the reuptake of 5hydroxytryptamine and norepinephrine, thereby increasing the levels of neurotransmitters such as 5-hydroxytryptamine and norepinephrine in the central nervous system, which is beneficial to the control of migraine and the improvement of mood.
N2 is the response inhibition wave, reflecting the time from receiving stimulation to response execution. P3a originates from the temporal parietal cortex, reflecting automatic attention; P3b originates from the hippocampus, reflecting active attention (Hashimoto et al., 2019). This study found that the amplitude of N2, P3a, and P3b in patients treated with flunarizine combined with duloxetine was higher than that in patients treated with flunarizine combined with loxoprofen sodium, and the latency of N2 and P3a was lower than that in patients treated with flunarizine combined with loxoprofen sodium, but there was no significant difference in the latency of P3b between the two TA B L E 4 Comparison of neuroelectrophysiological indexes (P3b) between the two groups (ŕχ ± s) Note: Compared with before treatment,*p < .05.

Number of cases
groups. This result suggests that flunarizine combined with duloxetine in the treatment of chronic migraine with comorbid depression and anxiety disorders can effectively improve the neurological function of patients. This is because duloxetine can activate 5-hydroxytryptamine and norepinephrine pathways, increase the release of brain-derived neurotrophic factors, restore neural plasticity, and promote nerve injury repair.
TNF-α is an early factor of inflammatory response, which can promote the release of proinflammatory factors such as IL-6 and further aggravate the inflammatory response (Guliyeva et al., 2020). hs-CRP is a sensitive inflammatory marker, which increases rapidly in trauma, inflammation, and infection (Hagen et al., 2020). The body of migraine patients was in a state of microinflammation, and the serum levels of TNF-α, IL-6, and hs-CRP were at a high level (Taheri et al., 2021). This study found that TNF-α, IL-6, and hs-CRP in patients treated with flunarizine combined with duloxetine were lower than those in patients treated with flunarizine combined with loxoprofen sodium. This result suggests that flunarizine combined with duloxetine in the treatment of chronic migraine with comorbid depression and anxiety disorders can reduce the inflammatory response.
In summary, flunarizine combined with duloxetine in the treatment of chronic migraine with depression and anxiety disorder comorbidity can effectively improve neuroelectrophysiological indexes, reduce inflammation, and alleviate depression and anxiety.

CONFLICT OF INTEREST
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

DATA AVAILABILITY STATEMENT
The datasets generated and analyzed during the current study are available from the corresponding author on reasonable request.