Abstract
Background
Migraine is characterized by unilateral head pain with episodic attacks interspersed with symptom-free periods. This recurring and disabling neurovascular condition affects 18% of women and 6% of men, with a global prevalence of 2% for chronic migraine.
Objective
This study aims to estimate the effectiveness of duloxetine in treating vestibular migraine.
Methods
The study included a total of 72 patients who were admitted to the Neurology department between January 2020 and January 2022. Based on the presence or absence of duloxetine in their medical records, the patients were categorized into two groups: a duloxetine group and a control group. Parameters used to assess treatment effects on vestibular symptoms included DHI, VSS, SAS, SRSS, SF-36, and BPI. Follow-up and statistical analysis of all data were performed.
Results
Duloxetine treatment significantly reduced VSS, the DHI total score, and the number of vertiginous episodes in VM patients, while the other medicine treatment also decreased the incidence of vertiginous attacks. However, the reduction in duloxetine group presented a better treatment effect and a lower occurrence of adverse reactions contrasted to the control group.
Introduction
Migraine is characterized by unilateral head pain with episodic attacks interspersed with symptom-free periods. 1 This recurring and disabling neurovascular condition affects 18% of women and 6% of men, with a global prevalence of 2% for chronic migraine. 2 Although early neurologists recognized the connection between migraine and dizziness in the nineteenth century, few studies have investigated vertigo caused by migraine. In the last three decades, vestibular migraine (VM) has emerged as a diagnostic label, affecting up to 1% of the general population. 3 As VM clinical criteria are established and validated, the term is now generally used to describe those patients with migraine-related symptoms such as vertigo, visual aura, photophobia (visually induced discomfort), and phonophobia (transient, sound-induced discomfort).
Despite the recognition of VM as a distinct neurological condition, there remains a significant gap in the understanding and effective management of this disorder. Current treatment recommendations for VM are largely extrapolated from studies on other migraine forms due to the limited data specific to VM. 3 This extrapolation leaves a substantial gap in targeted and effective treatment options for VM patients, leading to persistent issues in disease management and patient quality of life. Previous pharmacological treatments have shown limited efficacy in addressing the vestibular symptoms specifically associated with VM, highlighting the need for more specialized interventions.
The pathophysiology of vestibular migraine requires further elucidation. Previous study found the effect of the mediodorsal thalamus in pain processing and cortical excitability, which interconnect with the migraine circuit. 4 They suggested that a dysfunctional thalamocortical network disrupts vestibular, visual, proprioceptive, and somatosensory afferent inputs. Cutrer et.al. posited that dizziness unrelated to headaches results from the release of neuropeptides. 5 The research suggests that specific behavioral and dietary adjustments may offer potential benefits in the treatment and prevention of VM.6,7 Anti-migrainous medication is prescribed for patients who do not profit from these modifications as prophylactic treatment. Nevertheless, recommendations for managing vestibular migraine are generally extrapolated from studies on other forms due to limited data.
Given the intertwined role of serotonergic and noradrenergic systems in the regulation of neuropathic pain and potential migraine relief, antidepressants, particularly serotonin-norepinephrine reuptake inhibitors (SNRIs) like duloxetine, have been considered for migraine prevention.8,9 However, the specific role of duloxetine in treating VM has not been extensively explored. Prior studies have primarily focused on duloxetine's efficacy in general migraine prophylaxis but have not specifically addressed its impact on the vestibular symptoms that characterize VM. The aim of this study is to address the existing research gap by examining the efficacy of duloxetine in treating vestibular migraine, thereby enhancing current understanding and potentially providing a more targeted therapeutic approach for patients with VM.
Given that both serotonergic and noradrenergic systems regulate neuropathic and likely migraine pain, 8 antidepressants were among the earliest medications identified for migraine prevention.9,10 Recent studies have demonstrated that duloxetine, a kind of serotonin-norepinephrine reuptake inhibitor, is effective in modulating pain for migraine prevention. 11 Duloxetine is a chiral compound known as [(+/)-N-methyl-3-(1-naphthalenyloxy)-3(2-thiophene) propanamine], is synthesized by combining (S)-3-chloro-1-(2-thienyl)-1-propanol and other corresponding (R)-butanoate. 12 This compound functions as a potent inhibitor of the NE transporters and 5-HT, with approximate inhibition constants (Ki) of 0.8 nM and 7.5 nM, respectively. 12 Notably, it exhibits insignificant suppression of the dopamine transporter. The inhibition of NE transporters and 5-HT by duloxetine is more balanced compared to venlafaxine, with a binding ratio of approximately 10 for duloxetine and around 30 for venlafaxine. 12 Importantly, duloxetine exhibits minimal affinity for histamine-1, muscarinic, dopamine, adrenergic, and 5-HT receptors. 12
However, there is limited data currently on management strategies specifically for VM, and recommendations are often extrapolated from other forms of migraine. The objective of this study is to address the knowledge gap by investigating the efficacy of Duloxetine, a serotonin-norepinephrine reuptake inhibitor, in the treatment of VM. By establishing an open-label, placebo-controlled, prospective, randomized controlled trial (RCT), this study aims to propose valuable perceptions into the effectiveness of duloxetine in the prophylactic treatment of vestibular migraine. The findings of this study may have the enormous potential to make a significant contribution to the development of targeted treatment approaches for VM, improving the quality of life for patients affected by this condition.
Methods
Study design
In this study, we reviewed patients hospitalised in the Neurology department from January 2020 to January 2022. Participants were assigned to either the duloxetine group or the control group through a randomized process using computer-generated random numbers to ensure allocation concealment. The control group received a placebo medication matched for appearance and administration schedule with duloxetine. To ensure the validity of the study, blinding was maintained for both participants and researchers. This study adhered to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines to ensure quality and transparency in the reporting of methodologies and findings. Ethical approval was obtained from the institutional review board, and all participants provided informed consent prior to their inclusion in the study.
Participants were selected based on strict inclusion and exclusion criteria. The inclusion criteria encompassed patients who were diagnosed with vestibular migraine (VM) as per the International Classification of Headache Disorders (ICHD-3) guidelines. 6 Diagnosis was confirmed through a comprehensive clinical evaluation conducted by a neurologist specialized in vestibular disorders. This evaluation included a detailed medical history, headache characteristics, and vestibular symptoms such as vertigo and dizziness.
To distinguish VM from other vestibular and central nervous system pathologies, a series of diagnostic tests were performed. Audiological tests, including pure-tone audiometry and speech audiometry, were conducted to assess hearing function and rule out peripheral vestibular disorders. Additionally, caloric testing and video head impulse testing (vHIT) were performed to evaluate the integrity of the vestibulo-ocular reflex. 7
Moreover, to exclude central causes of vertigo, such as brain tumors or demyelinating diseases, all participants underwent radiological imaging. Magnetic resonance imagin(MRI) of the brain, with a focus on the posterior fossa, was performed for each patient. This imaging helped rule out any structural abnormalities that could mimic VM symptoms. In cases where MRI was contraindicated, computed tomography(CT) scans were used as an alternative imaging modality.
Sample size calculation
Prior to commencing the study, a sample size calculation was conducted in order to ensure adequate statistical power for detecting a clinically significant difference between the duloxetine and control groups. Based on previous studies on the efficacy of serotonin-norepinephrine reuptake inhibitors (SNRIs) in migraine management, a minimum detectable effect size of 0.5 standard deviations was assumed. With an alpha level of 0.05 and a power of 0.80, it was determined that a total of 60 participants would be needed, evenly divided between the duloxetine and control groups. Considering potential dropout rates, the target recruitment number was set at 70 participants.
Outcome assessment
This study evaluated the effectiveness of duloxetine compared with other medicine in improving vestibular symptoms in patients with VM. The total number of spontaneous vertiginous attacks was evaluated over a period of one week for each patient. The selected time frame was intended to facilitate a comprehensive evaluation of the frequency of vertigo and capture any potential variations in symptom occurrence. Patients were instructed to maintain a daily diary, recording each episode of spontaneous vertigo, including its duration and intensity.
According to previous migraine-related studies, the selection of evaluation metrics was motivated by the necessity to encompass a holistic representation of the impact of virtual machines.13,14 The Vertigo Severity Score (VSS) and Dizziness Handicap Inventory (DHI) were specifically chosen to quantify vertiginous symptoms and their functional repercussions. The SAS and self-rating Sleep Scale (SRSS) allowed for the assessment of commonly co-occurring anxiety and sleep disorders in VM patients. The short-form health survey (SF-36) provided a holistic measure of physical and mental health, while the Brief Pain Inventory (BPI) gave detailed insights into pain severity and its interference with daily activities. These metrics were administered at baseline, and at 16-week after treatment period in both groups. Data collection adhered to standardized protocols to ensure consistency and reliability.
Statistical analysis
Data were analyzed using SPSS software version 25.0 (IBM Corp, Armonk, NY). Continuous variables were expressed as mean ± standard deviation (SD) and compared using t-tests or Mann-Whitney U tests as appropriate. Categorical variables were compared using chi-square or Fisher's exact test. The primary analysis consisted of comparing the change in VSS and DHI scores from baseline to the end of the treatment period between the two groups. Secondary analyses included similar comparisons for SAS, SRSS, SF-36, and BPI scores. Missing data were addressed using multiple imputation methods to preserve the integrity of the dataset. All tests were two-tailed, with a significance level set at p < 0.05.
Clinical characteristics of subjects with clearly diagnosis of vestibular migraine.
Clinical characteristics of subjects with clearly diagnosis of vestibular migraine.
Baseline data of control and duloxetine group.
BMI: body mass index, VM: vestibular migraine, DHI: Dizziness Handicap Inventory, VSS: Vertigo Severity Score, SRSS: self-rating sleep scale, BPI: Brief Pain Inventory, SF-36: short-form health survey
Participants’ characteristics
In total, there were 63 participants (33 in the placebo group and 30 in the Duloxetine group) included in the study. The comprehensive clinical features of individuals diagnosed with vestibular migraine were presented in Table 1. The baseline characteristics exhibited no significant disparities among the treatment groups and were generally in line with the clinical manifestation of vestibular migraine(Table 2). Most patients were female, with a mean age of 30–39 years and a body mass index(BMI) range of 23–25. The average duration of symptoms was 18 months. Clinical characteristics for diagnosed patients typically encompassed vestibular symptoms(spontaneous/positional vertigo), additional symptoms(dizziness, oscillopsia, intolerance to head motion, vomiting, nausea), migrainous symptoms accompanying at least 50% of vertiginous attacks(headache, phonophobia, photophobia, visual aura), and cochlear symptoms(tinnitus, hearing loss, aural fullness, perceptual hearing loss). Clinical statistics also indicated that menstrual cycle, psychological stress, sleep disturbances, inadequate hydration, exposure to bright or flickering light, and dietary factors were the primary triggers.
Dizziness handicap inventory (DHI)
The DHI scores were significantly improved in the duloxetine treatment group compared to the control group. The mean change in DHI scores for physical symptoms was −3.13 ± 0.63 in the duloxetine group, which was significantly greater than the change of −1.03 ± 0.17 observed in the placebo group(p < 0.001). Similarly, the duloxetine group showed greater improvement in functional sympto(mean change of −2.53 ± 0.51) compared to the control group(mean change of −1.09 ± 0.29; p < 0.001). Additionally, emotional symptoms showed a greater decrease in the duloxetine group (mean change of −2.33 ± 0.66) compared to the control group(mean change of −0.61 ± 0.50; p < 0.001). Overall, the total DHI score improvement was significantly higher in the duloxetine group (mean change of −8.00 ± 0.95) compared to the control group(mean change of −2.73 ± 0.63; p < 0.001) (Table 3).
Treatment effect results used to assess outcome measures.
Treatment effect results used to assess outcome measures.
DHI: Dizziness Handicap Inventory, VSS: Vertigo Severity Score
The average number of vertiginous attacks per month was significantly reduced in the duloxetine treatment group compared to the control group. The duloxetine group showed a mean change of −2.89 ± 0.43 attacks per month, which was significantly greater than the change of −0.36 ± 0.49 attacks per month observed in the control group(p < 0.001). This finding suggests that duloxetine has a substantial impact on reducing the frequency of vertiginous attacks (Table 3).
Vertigo severity score (VSS)
The VSS scores also demonstrated significant improvement in the duloxetine treatment group compared to the control group. The mean change in VSS scores was −1.43 ± 0.50 in the duloxetine group, while the control group. showed a mean change of 0.33 ± 0.48(p < 0.001). These results indicate a clear positive effect of duloxetine treatment on vestibular symptoms (Table 3).
Self-rating depression scale (SDS) and self-rating anxiety scale (SAS)
After 16 weeks of treatment, the SAS score in Group D decreased from 60.03 ± 5.34 to 32.20 ± 4.05, and the SDS score decreased from 55.53 ± 4.88 to 36.50 ± 4.02. In Group P, the SAS score decreased from 59.87 ± 5.23 to 43.18 ± 4.31, and the SDS score decreased from 59.85 ± 5.17 to 43.18 ± 4.31. Group D patients demonstrated statistically significant reductions in anxiety and depression compared to Group P patients (P < 0.001). The treatment effect in Group D was obviously better than in Group P (Table 4).
Comparison of SDS and SAS scores before and after medication between the two groups. (x ± s, points)
Comparison of SDS and SAS scores before and after medication between the two groups. (x ± s, points)
SDS: Self-rating depression scale, SAS: Self-rating anxiety scale
During the study, only one patient in Group D experienced adverse reactions, primarily manifesting as dry mouth. In Group P, nine patients experienced adverse reactions, including two instances of dry mouth, three case of reduced appetite and four case of nausea. Notably, nausea was not found in Group D. Overall, the incidence of adverse reactions in Group P was markedly higher than in Group D (Table 5).
The incidence of adverse reactions in the two groups of patients.
The incidence of adverse reactions in the two groups of patients.
Mean daily pain intensity decreased to varying degrees in both groups over 16 weeks of continuous treatment. However, the reduction in pain intensity was significantly greater in Group D compared to Group P. Interestingly, the average daily pain intensity began to progressively increase in both groups starting from day 39 onwards; however, the underlying mechanism driving this observed trend remains elusive and necessitates further comprehensive investigation(Figure 1).
Comparison of the average daily pain intensity between the two groups (24-h average pain intensity rating, scored on a scale of 0–10).
The self-rating Sleep Scale (SRSS) was used to assess the patients, and after study, the the Brief Pain Inventory(BPI) and MOS item short-form health survey (SF-36) revealed that Group D experienced significantly fewer sleep problems and reduced pain intensity compared to Group P. Additionally, the risk of depression among patients in Group D was signally lower than in Group P. The overall health of patients in Group D was also considerably higher than in Group P, suggesting a better prognosis (Figure 2).
Self-Rating scale of sleep (SRSS), Brief Pain Inventory (BPI), and the MOS item short-form health survey (SF-36).
VM is a neurological disorder that causes vertigo in adults and frequently requires medical resources. Despite being the most prevalent neurologic cause of vertigo in adults, it is often misdiagnosed and unrecognized. 15 Antidepressants are commonly used as migraine prevention medications, and they are essential for the preventive treatment of migraines. Junliang Zhu et al. found that the combination of flunarizine and duloxetine effectively improved neuro-electrophysiological indices, reduced inflammation, and attenuated symptoms of depression and anxiety in the treatment of anxiety disorders and chronic migraine with comorbid depression. 16 The recent RCT on the effectiveness of duloxetine in preventing VM in patients was successful, as evidenced by our study showing significant improvements compared to placebo treatment. Additionally, the findings suggest that duloxetine treatment reduced the VSS, DHI total score, and frequency of vertiginous attacks, aligning with previous migraine research. This study provides valuable insights into the potential benefits of duloxetine in managing VM in patients.
The understanding and diagnosis of VM have also been enriched by the guidelines and diagnostic criteria established by the Barany Society. According to these criteria, key features for diagnosing vestibular migraine (VM) include experiencing at least five episodes of vestibular symptoms lasting between 5 min and 72 h, having a current or previous history of migraine, and presenting with at least one migraine feature during two or more attacks of vertigo. The comprehensive guidelines of the Barany Society emphasize the significance of differentiating VM from other potential causes of vestibular symptoms, thereby enhancing diagnostic accuracy and aiding clinicians in implementing appropriate treatment strategies. 17
The pathophysiology of vestibular migraine is currently not fully clearness. Some studies propose that environmental and genetic factors may contribute to its development. 18 Research suggests that vertigo during migrainous attacks may result from reduced blood flow to the inner ear, causing vasospasm. 19 This is supported by evidence linking migraines to an incremental risk of stroke and sudden sensorineural hearing loss.20–22 Acute migraine management includes medications such as antiemetics, non-steroidal anti-inflammatory drugs, and triptans. 23 Prophylactic treatment may involve beta-blockers, antiepileptic drugs, calcium channel blockers, antidepressants, antihypertensives, anti-serotonergic drugs, and monoclonal antibodies against CGRP.
Duloxetine is effective for chronic pain conditions like diabetic neuropathy, fibromyalgia, and irritable bowel syndrome. 24 Recent studies investigating duloxetine as a preventive migraine treatment (both chronic and episodic) have reported reductions in migraine days and attack frequency and a reduction in analgesic consumption for acute migraine. 25 Another double-blind RCT found duloxetine to be more effective than placebo in preventing migraines based on patients’ improvement evaluations. 11 The findings of this study suggest that duloxetine holds potential as a personalized therapeutic approach to augment the efficacy of migraine prevention treatment. However, pharmacologic management's efficacy for migraines may be inadequate for preventing or treating VM due to migraine treatment guidelines not assessing the curative effect of interventions for vestibular symptoms. Thus, there is still a need to develop practical management guidelines for vestibular migraine using the available evidence. Despite conducting Cochrane reviews, no placebo-controlled prospective clinical trials have been identified to evaluate the efficacy of various pharmacologic therapies for VM. 26 The study successfully met its primary endpoint. Our research involved 27 female and 6 male patients in the control group and 26 female and 4 male patients in the Duloxetine group. The results show that Duloxetine significantly improved treatment outcomes. Specifically, it reduced the VSS, DHI total score, and the number of dizzy episodes in VM patients. Additionally, with no reported deaths during the experiment. Interestingly, Pınar Özçelik et al. confirmed that being female was a significant risk factor for VM. 27
The potential mechanisms of action for duloxetine in VM therapy can be hypothesized based on its known pharmacologic profile. Duloxetine's inhibition of serotonin and norepinephrine reuptake is believed to modulate central pain pathways and affect pain perception, which may alleviate the vestibular symptoms associated with VM. 28 Additionally, duloxetine's neuroprotective properties and influence on neuroplasticity could contribute to its therapeutic effects by stabilizing neuronal circuits involved in vestibular processing and migraine pathophysiology. 29 The dual modulation of serotonergic and noradrenergic transmission has the potential to ameliorate the frequency and severity of vertigo attacks by restoring equilibrium within affected neural networks. 30
Recent advancements in the treatment of VM include new pharmacological interventions besides duloxetine. For instance, monoclonal antibodies targeting Calcitonin Gene-Related Peptide (CGRP) and CGRP receptors have shown promise in VM treatment. 30 These treatments specifically target the CGRP pathways, which are pivotal in migraine pathophysiology, and have demonstrated efficacy in reducing migraine days and vestibular symptoms. Compared to these newer treatments, duloxetine offers a different mechanism by modulating both serotonergic and noradrenergic systems. The indications for duloxetine may be particularly pertinent to patients who also exhibit comorbid depressive or anxiety disorders, wherein its antidepressant effects could confer additional advantages.
Recent systematic reviews and meta-analysis on VM treatments has highlighted various pharmacological and non-pharmacological therapies, including the effectiveness and limitations of calcium channel blockers, beta-blockers, and antiepileptic drugs.28,29 When comparing these treatment modalities, there are significant differences in efficacy, side effect profiles, and mechanisms of action. For instance, while calcium channel blockers like flunarizine are often used for their vestibular suppressing properties, duloxetine provides a broader approach by also addressing central pain pathways and comorbid mood disorders. The decision to use duloxetine versus other VM treatments could thus be influenced by the patient's overall clinical profile, including the presence of mood disturbances and the specific characteristics of their vestibular symptoms.
This study is subject to certain limitations, such as the potential for recall bias in both groups due to questionnaire-based identification of headache triggers, and the restricted sample size represents another constrain. Besides, a significant limitation of this study is the absence of comprehensive objective audiological tests such as videonystagmography (VNG) and pure tone audiometry. These tests play a critical role in accurately diagnosing vestibular pathologies and differentiating VM from other conditions with overlapping symptoms. The inclusion of these diagnostic modalities in future research could enhance the reliability of VM diagnoses and provide deeper insights into the vestibular dysfunctions present in patients, thus refining the assessment of treatment efficacy for interventions like duloxetine.
Conclusions
This study presents valuable insights into the potential effectiveness of duloxetine in the prevention of vestibular migraine. Our findings indicate that duloxetine treatment offers significant improvements in comparison to other medicine treatment, including a reduction in the VSS, DHI total score, and frequency of vertiginous attacks. These results align with previous research on migraine prevention and contribute to an increasing body of evidence that supports the apply of duloxetine in managing vestibular migraine.
Footnotes
Acknowledgments
The authors have no acknowledgments.
Ethics approval and consent to participate
The study was approved by the ethics committee of The Second Affiliated Hospital of Qiqihar Medical University and written informed consents were signed by the patients and/or guardians.
Funding
This study was supported by Clinical Research Fund Project of Qiqihar Academy of Medical Sciences (QMSI2021L-18) and Joint Guidance Project of Qiqihar City Science and Technology Program (LSFGG-2024061).
Conflict of interest
The authors declare that they have no conflict of interest.
Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.