Comorbidity with fibromyalgia predicted poorer outcomes in patients with chronic migraine on flunarizine: Prospective proof-of-concept study

Abstract

Aim

Fibromyalgia (FM) and chronic migraine (CM) are commonly comorbid. Clinical observations suggest patients with chronic migraine comorbid with fibromyalgia (CMFM) seem less responsive to migraine preventive treatment; however, evidence is still lacking. This study examined the responsiveness to migraine preventive treatment in patients with CM and CMFM.

Methods

Patients with CM and CMFM were prospectively recruited. None of them received migraine prevention prior to participation. Both groups were administered with flunarizine as migraine prevention and were asked to keep headache diaries. The CMFM group received additional standard treatment for FM concomitantly, predominately pregabalin. Treatment response was defined as ≧50% reduction in monthly headache days (MHDs) at the third month post-treatment compared with baseline.

Results

Eighty-four patients with CM (38.3 ± 11.5 years old, 93% female) and 38 with CMFM (40.2 ± 11.3 years old, 87% female) finished the study for final analyses. CMFM had more MHD and higher levels of depression and anxiety at baseline. After treatment, CM demonstrated better treatment outcomes (50% responder rate 52% vs. 32%, p = 0.033). The presence of FM in patients with CM increased the odds of non-converter to EM after controlling for baseline MHD using a logistic regression model (OR: 2.8 [1.1-7.1], p = 0.027). Comorbid FM in patients with CM showed limited improvement despite receiving standard treatments for both conditions.

Conclusion

This proof-of-concept research underscores the importance of clinicians recognizing FM in patients with CM since they are prone to poor responses to treatment.

Graphical abstract

This is a visual representation of the abstract.

Keywords

treatment responsiveness prognosis prophylactics fibromyalgia chronic migraine

Introduction

Chronic migraine (CM) is a debilitating neurological disorder that significantly impairs quality of life. According to the diagnostic criteria in the International Classification of Headache Disorders, 3rd edition (ICHD-3) (1), CM is defined as those with 15 or more days with headache per month for three or more months, of which eight or more days with migrainous features or respond to migraine-specific treatment. CM affects 1–2% of the population worldwide and around 2.5% of patients with episodic migraine (EM) progress to CM yearly (2). CM is often accompanied by a variety of comorbidities, such as fibromyalgia (FM). FM, on the other hand, is defined by widespread musculoskeletal pain, fatigue, and sleep disturbances, accompanied by symptoms such as cognitive difficulties and mood disturbances that affect 3.3–8.3% (3) of the population worldwide. Both conditions share a commonality in their complex pathophysiology, involving central sensitization, dysregulated pain processing, and alterations in neurotransmitter systems, particularly serotonin and norepinephrine (4 –6). The co-occurrence of CM and FM is frequently observed in clinical practice, and one Taiwanese study (7) suggests a bidirectional relationship between FM and migraine in general. As much as 35.6% of patients with CM were reported to also present with FM, and vice versa, 55.8% of patients with FM were reported to fulfill the criteria for migraine (8).

Chronic migraine comorbid with fibromyalgia (CMFM) presents a unique clinical challenge, as they experience heightened pain sensitivity, increased headache frequency and severity, and reduced treatment response. However, evidence on the disparities in migraine treatment response between patients with CM only and CMFM is lacking. While the complexities of treating CM and FM individually have been explored, there is limited evidence of how the coexistence of these conditions impacts treatment outcomes. In particular, disparities in migraine prevention effectiveness between patients with CM only and those with CMFM remain poorly understood. This knowledge gap is crucial to address, as it may inform personalized treatment approaches and improve clinical outcomes for individuals suffering from both conditions.

The primary aim of this study was to compare the treatment response between patients with CM and CMFM following routine preventive treatment for migraine. We hypothesized that patients with CMFM would exhibit a poorer response to migraine prevention compared to those with CM alone, even when both CM and FM were treated concomitantly. This investigation seeks to provide a clearer understanding of how these comorbid conditions interact in the context of migraine prevention and to identify potential barriers to effective management for CMFM patients.

Methods

Participants

Newly diagnosed preventive-naive migraine patients were recruited from Taipei Veterans General Hospital, a national tertiary medical center, from May 2016 to December 2019. The migraine diagnosis was based on the criteria in the ICHD-3 $β$ (9). For participants enrolled before the publication of the 2016 American College of Rheumatology (ACR) criteria (10), the FM diagnosis was based on the criteria of the 2010 ACR criteria (11). For those enrolled afterward, we applied the 2016 criteria accordingly. We retrospectively reviewed the 13 patients diagnosed with the 2010 criteria initially, and confirmed that they all met the 2016 criteria. The demographics and clinical profiles were collected by a specifically designed, semi-structured questionnaire, followed by face-to-face interviews with headache specialists. The CM patients fulfilled the following inclusion criteria: (a) willing to participate in the study, (b) aged between 20 and 60 yrs., (c) diagnosed with CM, and (d) occurrence of migraine before age 50. The exclusion criteria for CM patients were as follows: (a) acute worsening of headache, (b) concomitant secondary headache disorder (except for medication-overuse headache, MOH), and (c) a history of use of migraine preventive medications. The CMFM patients fulfilled the above criteria for CM as well as ACR criteria for FM. Both CM and CMFM were excluded if they had (a) a history of major systemic illness, such as uncontrolled hypertension, diabetes, chronic kidney disease, autoimmune disease, or malignancy, (b) a history of neurological disorders that may alter sensation, such as stroke or peripheral neuropathy, (c) a history of psychiatric illness or regular use of psychotropic agents, such as antidepressants, antipsychotics, or sedatives, (d) daily consumption of >20 cigarettes, (e) pregnancy or lactation, and (f) any obvious infection or inflammation over a period of at least one month before entering the study. All patients were asked to keep a headache diary prospectively. The Institutional Review Board approved the study protocol at the Taipei Veterans General Hospital (IRB-TPEVGH No. 2015-11-002B). All participants provided informed consent prior to participation. The study procedures followed the Declaration of Helsinki.

Procedures

The eligible patients were asked to keep a headache diary after enrollment to document their baseline headache profiles, including headache manifestations, medication use, headache intensity, and duration for four weeks. For patients with CMFM, the average bodily pain (aBP) assessed with a numeric rating scale (NRS) from 0 to 10 was also recorded daily on the diary. Only acute abortive medications were allowed during the 4-week baseline period. They all finished a series of questionnaires to evaluate their stress, mood, and the impact of headache. The patients were assigned to different treatment groups (either CM or CMFM group) based on clinical diagnosis, without any randomization. The patients in both CM and CMFM group were administered with flunarizine as the prophylactic treatment for migraine, the standard migraine prevention treatment suggested by the Taiwan Guidelines for Preventive Treatment of Migraine (12 –14). Besides flunarizine, patients with comorbid fibromyalgia (CMFM group) received standard treatment for FM, mostly pregabalin if not contraindicated, which started with 75 mg and was gradually titrated if patients reported no obvious adverse effects. The use of acute medications, such as simple analgesics, nonsteroidal anti-inflammatory drugs, triptans, and ergots, was permitted during the study period and was recorded in the headache diary. These patients were followed up with regularly in our outpatient department for three months and were asked to keep a headache diary during this study period.

Questionnaire-based interviews

The specifically designed questionnaire included several instruments to measure psychological disturbances, stress, and functional disabilities related to headache attacks. The Hospital Anxiety and Depression Scale (HADS) (15) was used to evaluate the anxiety and depression levels of the participants. The Perceived Stress Scale (PSS) (16) was used to assess the life stress of the participants. Migraine Disability Assessment (MIDAS) (17) evaluated the disability caused by migraine. The Headache Impact Test (HIT-6) (18) was used to assess the impact of headache on daily life. The revised Fibromyalgia Impact Questionnaire (FIQR) was used to evaluate the impact of FM on patients’ daily activities (19). Widespread Pain Index (WPI) and Symptom Severity Score (SSS) were also used to assess the severity of FM (20).

Outcome measures

Patients who provided at least one post-treatment outcome assessment were included in this intent-to-treat analysis. The primary outcome of the study is the 50% responder rate at the third month after treatment, defined as at least a 50% reduction in the monthly headache days (MHDs) following three-months preventive treatment as compared to baseline (M0). The secondary outcomes include the MHD at the first, second and third month (M1, M2, and M3) and the conversion rate to EM. The subjects included in the analyses had to complete the diary for at least 14 days every four weeks during the study period. The MHDs were calculated based on the percentage of headache days of the documented days. Last Observation Carry Forward (LOCF) was used for those missing the diary of the fifth to the twelfth week after the treatment. The same method was used for the calculation of aBP at each timepoint for patients with CMFM. The conversion to EM was defined as those who no longer fulfilled the diagnostic criteria (1) of CM in the third month after treatment.

Statistical analyses

All statistical analyses were performed in SPSS version 24.0 (IBM, Armonk, NY, USA). The data were presented as means with standard deviations (SDs) or standard errors (SEs) or numbers (%) when appropriate. The normality of data distribution was tested with Kolmogorov-Smirnov tests. Independent t-tests or Mann-Whitney U tests were used to compare the differences in demographics, psychosocial factors, and headache profiles between CM and CMFM at baseline. Categorical variables were compared using chi-square tests or Fisher's exact tests. Binary logistic regression analysis was used to examine the treatment responses. Mix-effect models with repeated measures and least significant difference (LSD) tests were used to compare the MHD between CM and CMFM at time points (M1, M2, M3) controlling for baseline MHD. In CMFM, the aBP was calculated for further comparison. A two-way mixed-design ANOVA was performed to examine the effects of time (within-subject factor: M0 and M3) and group (between-subject factor: migraine treatment responders vs. non-responders) on aBP. This model tested the main effects of time and group, as well as the group × time interaction effect. Post-hoc analyses were conducted using paired t-tests within groups and independent t-tests between groups. All tests were two-tailed, and the significance level was set at p < 0.05.

Results

Study participants and baseline characteristics

This study prospectively recruited 114 prophylactic-naive CM patients and 69 prophylactic-naive CMFM patients, and of them, 108 CM and 45 CMFM completed the baseline diary and assessment. Figure 1 shows the flow chart of the study. All participants completed at least one month of follow-up; 86.9% completed at least two months, and 73% completed the entire three-month study period. Among those who had completed the baseline diary and received treatment for migraine (both CM and CMFM) and fibromyalgia (for CMFM), 84 CM patients (38.3 ± 11.5 yrs., 93% female) and 38 CMFM (40.2 ± 11.3 yrs., 87% female) were included in the outcome analysis (completion rate = 77.8% and 84.4% for CM and CMFM, respectively). Table 1 shows the baseline demographics, psychosocial data, and headache profiles of the participants. Patients with CMFM had more MHD compared to patients with CM. They also demonstrated higher levels of depression, anxiety, widespread pain, and self-report severity of symptoms. Otherwise, the demographic data and the rest of the headache profiles, including BMI, headache history, MIDAS, HIT-6, and PSS, were comparable between CM and CMFM.

Figure 1.

The study flow chart.

Table 1.

Demographic and psychosocial data of subjects.

	CM	CMFM	p
N	84	38	-
Age (yrs.)^a	38.3 ± 11.5	40.2 ± 11.3	0.396
Sex (F%)	93%	87%	0.283
BMI (kg/m²)^a	23.1 ± 4.5	21.7 ± 3.1	0.375
Headache history (yrs.)^a	18.9 ± 11.5	19.4 ± 13.0	0.954
MIDAS^a	38.1 ± 46.4	58.3 ± 61.6	0.135
HIT-6^a	62.6 ± 5.3	60.1 ± 13.9	0.702
PSS^a	26.2 ± 8.1	29.4 ± 11.4	0.054
HASD-A	8.3 ± 3.9	11.1 ± 4.8	0.001*
HADS-D^a	5.9 ± 3.4	9.8 ± 4.5	<0.001*
FIQR	-	43.5 ± 16.0	-
WPI^a	2.6 ± 1.9	9.6 ± 4.2	<0.001*
SSS^a	5.1 ± 2.1	8.3 ± 2.4	<0.001*
MHD (d/m)^a	21.7 ± 6.0	25.6 ± 4.0	<0.001*
MOH (%)	23%	16%	0.387

Data presented as means and standard deviations. ^anot normally distributed, tested with Mann-Whitney U tests, *p < 0.05.

CM: chronic migraine, CMFM: chronic migraine comorbid with fibromyalgia, BMI: body mass index, MIDAS: Migraine Disability Assessment, HIT-6: Headache Impact Test, PSS: Perceived Stress Scale, HADS-A & HADS-D: Hospital Anxiety and Depression Scale, anxiety scale or depression scale, FIQR: Revised Fibromyalgia Impact Questionnaire, WPI: Widespread Pain Index, SSS: Symptom Severity Score, MHD: monthly headache day, MOH: medication-overuse headache.

Treatment outcomes

Participants in the CM group were placed on 6.7 ± 2.5 mg flunarizine per day, and those in CMFM had 6.0 ± 2.0 mg flunarizine and 125.0 ± 51.5 mg pregabalin per day. There was no significant difference in the dosage of flunarizine between CM and CMFM (p > 0.05). Patients with CM had a reduction of MHD from 21.7 ± 6.0 days at baseline to 12.4 ± 8.7 days at M3; on the other hand, patients with CMFM showed a reduction of MHD from 25.6 ± 4.0 days at baseline to 18.2 ± 9.8 days by M3 (Table 2). There were no differences between 50% treatment responders and non-responders in baseline demographics, psychosocial factors, and headache profiles (all p > 0.05) in CM (Online Supplementary Table E1) and CMFM (Online Supplementary Table E2) except for MHD in CM.

Table 2.

Headache profiles of the subjects.

	CM	CMFM	p
Baseline MHD (d/m)^a	21.7 ± 6.0	25.6 ± 4.0	<0.001*
M3 MHD (d/m)^a	12.4 ± 8.7	18.2 ± 9.8	0.006*
M3 50% responder rate	52%	32%	0.033*
Conversion to EM at M3	73%	37%	<0.001*

Data presented as means and standard deviations. ^anot normally distributed, tested with Mann-Whitney U tests, *p < 0.05.

CM: chronic migraine, CMFM: chronic migraine comorbid with fibromyalgia, MHD: monthly headache day, EM: episodic migraine, M3: the third month after treatment.

Primary outcome

There were 44 (52%) patients with CM and 12 (32%) patients with CMFM identified as treatment responders with ≥50% reduction of MHD in the third month compared to baseline based on their headache dairy. Patients with CM exhibit a higher proportion of treatment responders compared to those with CMFM (52% vs. 32%, p = 0.033) (Table 2). The presence of comorbid FM was associated with poor migraine prevention outcomes (odd ratio (OR): 2.4, 95% confidence interval (CI): 1.1 $-$ 5.3, p = 0.035). We conducted an additional logistic regression to control the potential confounding effects of the baseline psychological disorders. Based on our previous studies validated in Taiwanese migraine patients, a total HADS score of ≥10 was used as the cut-off for defining psychological disorders, including depressive and anxiety disorders, given its established sensitivity and specificity. After controlling for the presence of psychological disorders, FM remained significantly associated with an increased risk of non-response (OR: 2.4, 95% CI: 1.1 $-$ 5.4, p = 0.035). It was noteworthy that the presence of psychological disorders was not significantly associated with treatment response (p = 0.934), suggesting that psychopathological comorbidity did not account for the observed differences between CM and CMFM (Online Supplementary Table E3).

Secondary outcomes

Because the baseline MHD was not equivalent between the two groups, we further investigated whether this could contribute to the treatment outcome. Mix-effect models with repeated measures showed less MHD in patients with CM compared to patients with CMFM at M2 (14.9 [SE: 0.8] vs. 18.4 [SE: 1.2] days, p = 0.022) and a trend at M3 (13.4 [SE: 0.8] vs. 16.0 [SE: 1.2] days, p = 0.082) after controlling for baseline MHD (Figure 2).

Figure 2.

The monthly headache days in cm and CMFM.

The conversion rate to EM was significantly higher in patients with CM compared to those with CMFM (73% vs. 37%, p < 0.001) (Table 2). The same results were identified, showing that the presence of FM increased the odds of non-converters (i.e., persisted to have CM) after controlling for baseline MHD using a logistic regression model (OR: 2.8, 95% CI: 1.1 $-$ 7.1, p = 0.027).

The aBP was assessed in CMFM at M0 and M3 (Online Supplementary Table E4). While there was no significant difference between responders and non-responders at baseline (post-hoc p = 0.084), responders demonstrated significantly lower bodily pain scores across time compared to the non-responders (group main effect: p = 0.022). A significant overall reduction in bodily pain was also observed over time (time main effect p < 0.001). Post-hoc analyses showed significant within-group improvements in both responders (3.7 ± 1.4 to 1.8 ± 1.2, p = 0.001) and non-responders (4.8 ± 2.0 to 4.0 ± 2.4, p = 0.033). However, the group × time interaction was not statistically significant (p = 0.140), indicating that the extent of improvement over time did not significantly differ between responders and non-responders.

Discussion

In this proof-of-concept prospective study, we found that CM patients with FM showed limited improvement in headache frequency despite receiving standard treatments for both conditions. This finding highlights the importance for clinicians to identify comorbid FM in patients with CM, as these patients tend to be more resistant to treatment. For headache researchers, the presence of other pain disorders, particularly FM, should be carefully cogitated when conducting clinical trials due to their potential interference with headache treatments. To the best of our knowledge, this is the first study that directly compared the efficacy of standard migraine prevention in patients with CM and CMFM with a prospective design to investigate how comorbid FM affects treatment outcomes.

FM is one of the most common comorbidities in patients with migraine; the ratio has been reported to range from 18% to as high as 35.6% in CM (7,21 –25). In clinical practice, the comorbidity between CM and FM presents a significant challenge due to the complex symptomatology and overlapping pathophysiological mechanisms of these two diseases. Some studies (7,8), including ours, have reported a bidirectional relationship between these two conditions, suggesting a shared neurobiological basis involving central sensitization, dysfunctional pain processing, and alterations in neurotransmitter pathways. Previous studies have also reported the comorbidity of FM in patients with CM to be associated with increased suicidal ideation/risks (26), headache frequency (26 –28) and severity (29), and reduced quality of life (30). Therefore, recognizing and addressing this comorbidity is essential in clinical practice to optimize treatment strategies, improve patient outcomes, and enhance overall healthcare management. Herein, we provided evidence of limited improvement in headache preventive treatment in CMFM patients, indicated by a significantly lower 50% responder rate at 32% compared to that of CM patients at 52%. Moreover, the conversion percentage to EM was also significantly lower at 37% compared to 73% in CM patients. Of note, the 50% responder rates of the current study were relatively high, especially in the CM group; this may be because we recruited patients naive to any migraine preventive treatments and potentially higher placebo effects in a specialized headache clinic setting.

Our prospective study provides results based on a direct comparison of CM and CMFM to emphasize the effect of comorbid FM in migraine treatment. We confirmed that the presence of FM increased the odds of poor response to flunarizine as migraine prevention as indicated by a lower 50% responder rate. Only one retrospective study (31) found a slightly higher proportion of comorbid FM in 12-month non-responders of onabotulinumtoxinA compared to responders, although without statistical significance (17.3% vs. 11.8%, p = 0.072). Further study is needed to investigate whether the association between poor treatment responses and comorbid FM remains true across different spectra of migraine prophylactics.

Flunarizine, instead of topiramate, was administered as migraine prevention treatment in the current study. Although not commonly used in the United States, flunarizine stands as a drug of choice for migraine prevention, both in Europe and Asia. The recommendations of the European Federation of Neurological Societies suggested flunarizine as a prophylactic treatment for migraine with level A evidence (32). The Medical Treatment Guidelines for Preventive Treatment of Migraine published by the Taiwan Headache Society (14), also recommended both flunarizine and topiramate as the first-line preventive treatment for migraine. The efficacy of flunarizine on migraine prevention in our population was demonstrated by a randomized, controlled study (33), which directly compared the treatment effect and adverse events of flunarizine and topiramate in patients with CM. The results suggested that flunarizine was more effective than topiramate in CM with good tolerance, which is another reason we prefer not to use topiramate. Based on past clinical experience and literature (34,35), a high proportion of patients experience side effects from topiramate, leading to self-discontinuation of the medication. Hence, we chose flunarizine as the preventive treatment for CM in this study. The dosage of pregabalin in the CMFM group may seem relatively low at around the lowest recommended dose. Based on our clinical experiences and previous study (36), which analyzed the nationwide database, the current dosage for pregabalin lies within the normal range for treating FM. In addition, a study (37) revealed that compared to Caucasian cohorts, Asian populations were less tolerant of adverse effects such as dizziness, somnolence, and weight gain. Hence, the current dosage of pregabalin is reasonable and optimal in our population.

In patients with CMFM, we assessed the changes of bodily pain before and after treatment for both conditions. We found no significant difference in baseline bodily pain scores between those who responded to migraine treatment and those who did not, suggesting that the baseline severity of bodily pain may not be a reliable predictor of migraine treatment outcomes in individuals with CMFM. Regardless of the response to flunarizine, all patients with CMFM experienced significant improvements in bodily pain following standard fibromyalgia treatment. This indicates that our fibromyalgia management approach was adequate and contributes to the robustness of our findings. Although a numerically greater reduction in bodily pain scores was observed in patients who responded well to migraine prevention, the extent of improvement was not statistically different from that seen in non-responders. This may indicate that migraine relief does not necessarily translate to substantial improvement in bodily pain in patients with CM.

Prior studies have reported elevated calcitonin gene-related peptide (CGRP) levels in patients with FM, suggesting a potential shared pathophysiological mechanism between migraine and FM (38,39). Our finding that comorbid FM is associated with poorer treatment outcomes in patients receiving flunarizine raises an important clinical question: do migraine patients with coexisting FM exhibit differential responses to CGRP-targeted therapies, such as CGRP monoclonal antibodies (mAbs)? Some randomized controlled trials (RCTs) evaluating the efficacy of CGRP mAbs have excluded patients with FM (40 –47). If comorbid FM compromises treatment outcomes with CGRP mAbs, then conducting appropriate stratification based on FM comorbidity would be essential to accurately evaluate treatment efficacy. This consideration highlights one of the key clinical implications of the present study: comorbid FM may attenuate the effectiveness of preventive therapies for migraine and should be explicitly addressed in the design and interpretation of future RCTs for migraine treatment. An even more provocative question is whether CGRP-specific therapies might have therapeutic potential for FM itself. A phase II randomized controlled trial investigating the efficacy of fremanezumab in FM may offer some insight (NCT03965091). This trial was terminated early following an interim analysis, as no significant differences were observed between the placebo and treatment groups (across two dosing regimens) in key FM outcomes, including the FIQR, patient global impression of change (PGIC), sleep quality, and other measures. Although current clinical evidence does not support the effectiveness of CGRP monoclonal antibodies in the treatment of FM, it remains worthwhile to explore the potential role of other CGRP-specific therapies, such as gepants, in managing FM symptoms.

Our study has limitations. First, for proof-of-concept, we recruited only patients devoid of major systematic diseases or previous use of migraine prophylactics. Whether these findings can be extrapolated to populations with these conditions necessitates further investigation. Second, we were unable to isolate the potential impact of anxiety and depression levels on treatment outcomes. However, we perceive the higher levels of anxiety and depression as the nature of FM and none of our participants had major psychiatric disorders. Hence, we did not attempt to balance the levels of anxiety and depression between CM and CMFM. Third, the sample size of the CMFM group is relatively small. However, this proof-of-concept study provides evidence and delineates the limited treatment response to migraine preventives in CM patients with FM. Lastly, as indicated above, the results of this study cannot be extrapolated to other migraine prophylactics, for example, tricyclic antidepressants, anticonvulsants, or anti-calcitonin gene-related peptide monoclonal antibodies, etc. Future studies that include these preventions are warranted.

Conclusion

Patients with CM comorbid with FM showed limited improvement in headache despite receiving standard treatments for both conditions. This finding emphasizes the importance for clinicians to identify patients with migraine who also have fibromyalgia, as these patients are often more treatment-resistant. A comprehensive approach incorporating multidisciplinary treatment strategies tailored to consider both conditions concurrently may be required to effectively manage the complex symptom burden and enhance the quality of life for these patients. On the other hand, when conducting clinical trials, the presence of comorbidities such as FM and other pain disorders should be contemplated, given their potential to interfere with the efficacy of headache treatment. Clinical implications

Patients with CM and comorbid FM exhibited limited improvement despite receiving standard treatments for both conditions.

CMFM patients experienced less reduction in headache frequency and a lower conversion rate to EM compared to those with CM alone.

A multidisciplinary treatment approach addressing both conditions simultaneously may be beneficial for these patients.

Supplemental Material

sj-docx-1-cep-10.1177_03331024251353412 - Supplemental material for Comorbidity with fibromyalgia predicted poorer outcomes in patients with chronic migraine on flunarizine: Prospective proof-of-concept study

Supplemental material, sj-docx-1-cep-10.1177_03331024251353412 for Comorbidity with fibromyalgia predicted poorer outcomes in patients with chronic migraine on flunarizine: Prospective proof-of-concept study by Yu-Hsiang Ling, Li-Ling Hope Pan, Shih-Pin Chen, Wei-Ta Chen, Hung-Yu Liu, Shuu-Jiun Wang and Yen-Feng Wang in Cephalalgia

Footnotes

Acknowledgements

We would like to thank all our participants for their active participation to the study. This work was supported by the Brain Research Center, National Yang Ming Chiao Tung University, from the Featured Areas Research Center Program within the framework of the Higher Education Sprout Project by the Ministry of Education of Taiwan.

Authors’ contributions

LLHP and YFW had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. SJW, SPC, WTC, HYL, and YFW were involved the study conception and design. YHL and LLHP were responsible for acquisition, analysis, and interpretation of data and were responsible for manuscript drafting. YHL, LLHP, SPC, WTC, HYL, YFW, and SJW contributed to critical revision of the manuscript for important intellectual content. All authors provided the final approval of the version to be published.

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding authors on reasonable request.

Declaration of conflicting interests

The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: SJW has received honoraria as a moderator from AbbVie, Biogen, Eli-Lilly, Hava Biopharma, and Pfizer, has received consulting fees from AbbVie, Eli-Lilly Taiwan, Percept Co., and Pfizer Taiwan, and has been the PI in trials sponsored by Eli-Lilly, Lundbeck, Novartis, and Pfizer Taiwan. He has received research grants from Taiwan branches of Eli Lilly, Novartis, and Orient Europharma.

Ethics approval and consent to participate

The Institutional Review Board approved the study protocol at the Taipei Veterans General Hospital (IRB-TPEVGH No. 2015-11-002B). All participants provided informed consent prior to participation. The study procedures followed the Declaration of Helsinki.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the National Science and Technology Council, Taipei Veterans General Hospital, (grant number 110-2321-B-010-005, 111-2314-B-A49-090-MY3, 111-2321-B-A49-004, 111-2321-B-A49-011, 112-2314-B-A49-013, 112-2321-B-075-007, 113-2314-B-A49-026, 113-2321-B-A49-017 , V114C-081, V114E-002-1 ).

ORCID iDs

Yu-Hsiang Ling

Li-Ling Hope Pan

Shih-Pin Chen

Hung-Yu Liu

Shuu-Jiun Wang

Yen-Feng Wang

Supplemental material

Supplemental material for this article is available online.

Notes

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