Clinical Response to Premonitory-Phase Goreisan Therapy in Migraine with Weather- and Barometric Pressure-Related Headache

Abstract

Goreisan has long been prescribed for weather- and barometric pressure-related headache. However, its efficacy when initiated during the premonitory phase of migraine has not been systematically evaluated. We retrospectively reviewed 81 patients diagnosed with migraine (mean age: 41.7 ± 11.5 years; 14.8% male). Subtypes included migraine with aura (MA, n = 1), without aura (MO, n = 72), and combined type (MA + MO, n = 8). Patients who received Goreisan monotherapy during the premonitory phase were categorized as consistent responders (CRs) or inconsistent responders (IRs). Clinical characteristics and treatment responses were compared between the two groups. The overall response rate to Goreisan was 61.7% (n = 50). Headache profiles and the efficacy of triptans did not differ significantly between CRs and IRs. However, psychiatric comorbidities were more frequent in IRs than in CRs (p = 0.011). Initiating Goreisan during the premonitory phase appears to be an effective therapeutic approach for migraine patients with weather- and barometric pressure-related headache. Clinical background, including psychiatric history, may influence treatment outcomes and should be considered when selecting patients for this strategy.

INTRODUCTION

Migraine is a common neurological disorder that causes substantial disability and significantly impairs quality of life. In Japan, the prevalence of migraine is estimated to be 8.4–8.6%.^1,2) Various triggers, including stress, irregular diet, sleep disturbance, menstruation, and changes in weather and barometric pressure, have been identified.^3–5) While some of these triggers can be managed by patients themselves, weather- and barometric pressure-related headaches remain difficult to control.

Japanese herbal Kampo medicines, such as Goreisan, Goshuyuto, and Kakkonto, are listed as empirically effective options in the Japanese Clinical Practice Guidelines for Headache 2021.⁶⁾ Goreisan, a formula composed of Alismatis rhizoma, Atractylodis lanceae rhizoma, Polyporus, Poria, and Cinnamomi cortex, is widely used for migraines, tension-type headaches, and secondary headaches. Experimental studies suggest that Goreisan modulates water metabolism by inhibiting aquaporin-4 activity, thereby reducing cerebral edema in animal models.⁷⁾ Clinically, it is used both prophylactically and as needed for headaches related to weather and barometric pressure.⁶⁾

The time course of migraine attacks includes premonitory, aura, headache, and postdrome phases.^8,9) Premonitory symptoms such as stiff neck and shoulders, photophobia, and phonophobia often precede migraine onset.⁹⁾ Our previous survey showed that many patients with weather- or barometric pressure-related headache reported premonitory symptoms, particularly neck and shoulder stiffness.¹⁰⁾ These observations suggest that early intervention at the premonitory phase could allow patients to mitigate the onset or severity of attacks. Some of these patients used Goreisan at the onset of such symptoms, suggesting the potential of a premonitory-phase treatment strategy. However, the clinical efficacy of initiating Goreisan during the premonitory phase has not been systematically investigated, and factors associated with treatment response remain unclear.

Therefore, the aim of the present study was to evaluate the efficacy of Goreisan initiated during the premonitory phase in migraine patients with weather- and barometric pressure–related headache, and to identify clinical factors, including premonitory symptom recognition, that may predict treatment response.

METHODS

Subjects

The cohort consisted of 81 patients with migraine as their initial headache who were prescribed Goreisan (TJ-17, 2.5 g/time, 7.5 g/day) as short-term preventive therapy for weather- and barometric-induced headache by specialists in the Japanese Headache Society. Patients were admitted to the outpatient clinic of Kuramae Kato Medical Clinic, Tokyo between June 2017 and April 2022. The patients took Goreisan from the premonitory period. Headache was diagnosed according to the International Classification of Headache Disorders, Third Edition criteria.¹¹⁾ Patients with medication-overuse headache (MOH) or with chronic migraine (CM) were asked about their initial headache by specialists, who also confirmed the initial headache and type of episodic migraine after treating the patients for MOH or CM. MOH patients were included if they had migraine as their initial headache. Although the cohort included patients with migraine and those with both migraine and tension-type headaches, patients with tension-type headache were excluded from this study.

According to their clinical response to Goreisan, patients were divided into consistent responder (CR) and inconsistent responder (IR) groups. The patients were asked whether their headaches diminished following Goreisan therapy from the premonitory period. Patients whose pain score improved to 50% or less compared to before treatment were judged to have received effective treatment, whereas those whose pain score was less than 50% were judged to have received ineffective treatment. Pain scores were assessed using a numerical rating scale (NRS), where 0 indicated no headache and 10 represented the maximum pain ever experienced by the patient. Consistent responders were defined as patients who experienced a ≥50% reduction in average NRS score across multiple migraine attacks. Attack frequency was not considered in this definition. Patients who did not meet this threshold were categorized as inconsistent responders. Patients who used Goreisan in combination with Goshuyuto (n = 92) and those who did not return for follow-up visits (n = 17) were excluded from the study, resulting in a final enrollment of 81 out of 190 patients.

Clinical responses to triptans were determined according to the responses of the responders and non-responders. Responders treated with triptans were defined as those with diminished pain described as either “mild” (within 4 h of oral or nasal administration) or “none” (within 2 h of oral or nasal administration) in at least 2/3 attacks.^12-14) Patients whose pain was not alleviated in three consecutively treated migraine attacks were defined as non-responders.

This clinical research was conducted after obtaining approval from the Human Subject Research Ethics Committee of Teikyo Heisei University (approval number: 30-115-1). The patients were informed that they are able to opt out from the use of their data for research purposes at the bulletin board in the clinic. This study was performed in accordance with the principles of the Declaration of Helsinki.

Clinical Parameters

For medical examinations, we used headache diaries and/or headache questionnaires to obtain pain location, headache characteristics, and frequency of headache and associated symptoms, and confirmed these by interview. In the case of MOH, we confirmed the initial headache and type of episodic migraine after curing the patients of MOH or CM.

The data collected from all patients were as follows: age, sex, current type of headache being treated, initial headache, type of episodic migraine, trigger of migraine, and history before the commencement of Goreisan treatment. In addition, we collected data on headache characteristics and frequency, location of pain, and associated symptoms before treatment. We investigated the use of prophylactic drugs and use of acute treatment drugs, such as triptans, when using Goreisan. Furthermore, we investigated the reduction of headache by Goreisan.

Statistical Analysis

For continuous variables, statistical analyses were conducted with F test followed by Student’s t test. For categorical variables, χ² test or Fisher’s exact test was conducted. Fisher's exact test was utilized when the sample size was small with expected frequency less than five in one cell. p < 0.05 was considered significant. The statistical software used was Excel Statistics ver. 3.21 (Social Information Service).

RESULTS

Patient Characteristics

The study population consisted of 81 patients with migraine as their initial headache (age, 41.7 ± 11.5 years), consisting of 12 (12.1%) men and 69 (87.9%) women. In total, 81 individuals had migraines with the following characteristics: one patient with aura (MA), 72 patients without aura (MO), and 8 patients with combined type (MA + MO). The efficacy of Goreisan (CR ratio) was 61.7% (n = 50) for these 81 patients (Table 1).

Table 1. Background of Patients

Factors Associated with Clinical Response to Goreisan

The frequencies of past histories of psychiatric disorders was significantly different between the CR and IR groups (p = 0.011, Table 1). The clinical profile of headache was not different between the CR and IR groups (Table 2). No intergroup difference was detected for the use or efficacy of triptans (Table 3). Edema was observed in three patients in the CR group and three patients in the IR group when Goreisan was prescribed (p = 0.670, data not shown).

Table 2. Clinical Profile of Headache

Table 3. Use of Triptans

DISCUSSION

Katsuki et al. reported an 83.1% efficacy rate for acute treatment using Goreisan in 71 cases of weather-related migraine.¹⁵⁾ However, the proportion of female subjects was 50.7%, and the criteria for judging efficacy were not provided. On the other hand, in the present study, efficacy was 61.7% and 85.2% of subjects were women who took Goreisan upon experiencing premonitory symptoms. The difference in responder rates between this study (61.7%) and the previous report by Katsuki et al. (83.1%) may be due to methodological differences, including the timing of Goreisan administration, the definition of efficacy, and population characteristics such as sex distribution. This difference in diagnostic inclusion criteria may also have contributed to the discrepancy in responder rates. Although the overall efficacy rate was lower than previously reported, this study suggests a potential clinical value of initiating Goreisan during the premonitory phase, as an association was observed between early administration and improved management of migraine attacks. However, given the retrospective nature of the study, causality cannot be established.

Migraine patients are known to be particularly prone to developing MOH as a comorbidity.¹⁶⁾ We previously reported that the incidence of depression is significantly higher in MOH patients than migraine patients.¹⁷⁾ Moreover, we reported that the complication of depression caused by another psychiatric disorder, such as panic disorder or personality disorder, contributed to the negative response to prophylactic therapy using valproate in migraine patients.¹⁸⁾ In the present study, psychiatric comorbidities were associated with a reduced response to Goreisan; however, this trend is consistent with other migraine treatments and should be considered a general limitation rather than a specific drawback of Kampo therapy.

The overuse of acute treatment drugs, such as NSAIDs and triptans, has become a concern; however, there have been no reports of MOH caused by Kampo such as Goreisan. MOH is an intractable headache that recurs repeatedly,¹⁹⁾ and most MOH patients initially had migraine.¹⁶⁾ Ishikawa et al. reported that the combined use of Western prophylactics and Kampo, such as Goreisan, contributes to successful withdrawal from causative drugs.²⁰⁾ In Japan, Teirakku, an over-the-counter drug of Goreisan, is taken when the patient feels unwell such as when the weather turns bad (Kobayashi Pharmaceutical Co.).²¹⁾ The recommended timing of administration of Goreisan is the same as in this study, in which it is taken from the premonitory period. These findings indicate that premonitory-phase Goreisan therapy was associated with reduced migraine frequency and may help prevent MOH, particularly in patients who are able to recognize early premonitory symptoms. However, this association should be interpreted with caution due to the retrospective design of the study.

The most important contribution of the present study is the demonstration that initiating Goreisan during the premonitory phase can be an effective therapeutic strategy for weather- and barometric pressure-related migraine. This study had several limitations. First, the sample size was small, and it was conducted at a single clinic; therefore, a multi-institutional approach is needed for validation of our findings. Second, the study had a retrospective design. Future studies with a larger sample size are warranted to confirm the reproducibility of our findings and allow for more robust statistical modeling. Third, pain reduction was assessed using NRS, rather than a formally validated tool such as the Visual Analogue Scale (VAS). This may raise concerns regarding reproducibility. However, NRS is widely used in clinical practice due to its simplicity and ease of understanding for patients, and was considered appropriate for this real-world study. In future studies, it will be important to stratify patients based on psychiatric comorbidities and to evaluate whether combining Goreisan with other Kampo medicines can further enhance therapeutic outcomes.

Acknowledgments

This study was supported by a grant (Grant-in-Aid for Scientific Research (C), 21K06693) from the Ministry of Education, Culture, Sports, Science and Technology. We thank Haruka Yui and Sae Yanagawa, students at Teikyo Heisei University, for their technical assistance. The authors would like to thank Medical English Service (https://www.med-english.com/support) for the English language review. The authors have no potential conflicts of interest to disclose.

Conflict of interest

The authors declare no conflict of interest.

REFERENCES

• 1)    Sakai  F,  Igarashi  H. Prevalence of migraine in Japan: a nationwide survey. Cephalalgia, 17, 15–22 (1997).
• 2)    Hirata  K,  Ueda  K,  Komori  M,  Zagar  AJ,  Selzler  KJ,  Nelson  AM,  Han  Y,  Jaffe  DH,  Matsumori  Y,  Takeshima  T. Comprehensive population-based survey of migraine in Japan: results of the ObserVational Survey of the Epidemiology, tReatment, and Care Of MigrainE (OVERCOME [Japan]) study. Curr. Med. Res. Opin., 37, 1945–1955 (2021).
• 3)    Kelman  L. The triggers or precipitants of the acute migraine attack. Cephalalgia, 27, 394–402 (2007).
• 4)    Park  JW,  Chu  MK,  Kim  JM,  Park  SG,  Cho  SJ. Analysis of trigger factors in episodic migraineurs using a smartphone headache diary applications. PLoS One, 11, e0149577 (2016).
• 5)    Ishii  M,  Katoh  H,  Yamada  C,  Takagi  M,  Ichikawa  M,  Kurihara  T,  Kawamura  M. Influence of the Great East Japan Earthquake on patients with migraine headaches in the Tokyo metropolitan area. Stress Sci. Res., 29, 43–51 (2014). (text in Japanese with English abstract)
• 6)   Japanese Headache Society. Japanese Clinical Practice Guidelines for Headache 2021. <https://www.jhsnet.net/pdf/guideline_2021.pdf> cited 21 July 2025.
• 7)    Yano  Y,  Yano  H,  Takahashi  H,  Yoshimoto  K,  Tsuda  S,  Fujiyama  K,  Izumo-Shimizu  Y,  Motoie  R,  Ito  M,  Tanaka  J,  Ishii  E,  Fukuda  M. Goreisan inhibits upregulation of aquaporin 4 and formation of cerebral edema in the rat model of Juvenile hypoxic-ischemic encephalopathy. Evid. Based Complement. Alternat. Med., 2017, 3209219 (2017).
• 8)    Blau  JN. Migraine: theories of pathogenesis. Lancet, 339, 1202–1207 (1992).
• 9)    Charles  A. The evolution of a migraine attack - a review of recent evidence. Headache, 53, 413–419 (2013).
• 10)    Ishii  M,  Ito  I,  Katoh  H. Investigation on headache caused by weather and atmospheric pressure changes and use of goreisan. Jpn. J. Soc. Pharm., 42, 17–25 (2023). (text in Japanese with English abstract)
• 11)   Headache Classification Committee of the International Headache Society (IHS). The International Classification of Headache Disorders, 3rd edition. Cephalalgia, 38, 1–211 (2018).
• 12)    Ishii  M,  Sakairi  Y,  Hara  H,  Imagawa  A,  Shimizu  S,  Takahashi  J,  Nagamine  A,  Naito  Y,  Masuda  Y,  Usami  S,  Kiuchi  Y. Negative predictors of clinical response to triptans in patients with migraine. Neurol. Sci., 33, 453–461 (2012).
• 13)    Ishii  M,  Katoh  H,  Kurihara  T,  Kawamura  M,  Shimizu  S. Characteristics of inconsistent responders to prophylaxis therapy with lomerizine in patients with migraine: a retrospective study in Japan. J. Neurol. Sci., 335, 118–123 (2013).
• 14)    Naito  Y,  Ishii  M,  Ishibashi  M,  Kasai  H,  Katoh  H. Negative predictors of clinical response to amitriptyline in Japanese patients with migraine. Neurol. Clin. Neurosci., 6, 125–130 (2018).
• 15)    Katsuki  M,  Narita  N,  Matsumori  Y,  Ishida  N,  Watanabe  O,  Cai  S,  Tominaga  T. Kampo (Japanese herbal) medicine for primary headache as an acute treatment: a retrospective investigation in Kesennuma City Hospital during five years. J. Neurosug. Kampo Med., 7, 1–7 (2022).
• 16)    Imai  N,  Kitamura  E,  Konishi  T,  Suzuki  Y,  Serizawa  M,  Okabe  T. Clinical features of probable medication-overuse headache: a retrospective study in Japan. Cephalalgia, 27, 1020–1023 (2007).
• 17)    Onaya  T,  Ishii  M,  Katoh  H,  Shimizu  S,  Kasai  H,  Kawamura  M,  Kiuchi  Y. Predictive index for the onset of medication overuse headache in migraine patients. Neurol. Sci., 34, 85–92 (2013).
• 18)    Ichikawa  M,  Katoh  H,  Kurihara  T,  Ishii  M. Clinical response to valproate in patients with migraine. J. Clin. Neurol., 12, 468–475 (2016).
• 19)    Katsarava  Z,  Muessig  M,  Dzagnidze  A,  Fritsche  G,  Diener  HC,  Limmroth  V. Medication overuse headache: rates and predictors for relapse in a 4-year prospective study. Cephalalgia, 25, 12–15 (2005).
• 20)    Ishikawa  R,  Kawamura  T,  Kohno  J. Traditional Japanese Kampo medicines contribute to successful withdrawal from the causative drug in medication overuse headache. Jpn. J. Headache, 48, 585–590 (2022).
• 21)   Kobayashi Pharmaceutical Co. Ltd. Kampo product Teirakku. <https://www.kobayashi cited 3 March, 2025.co.jp/seihin/otc_seihin/pdf/teirakku_en.pdf> cited 21 July 2025.