Abstract
Background
Almost one-third of patients with migraine do not adequately respond to triptans. We examined factors contributing to frovatriptan response in patients with migraine.
Methods
We enrolled new patients with migraine who consecutively visited our headache clinic. Eligible patients were instructed to take 2.5 mg of frovatriptan as soon as possible after migraine attack. The responsiveness was determined by whether headache was relieved or absent within 4 hours after the intake of frovatriptan. We assessed frovatriptan to be efficacious when headache responded to its administration in at least one of two successive migraine attacks and inefficacious when headache was not relieved in either attack. We included demographic, clinical and psychiatric variables in the analysis of factors associated with frovatriptan response.
Results
Of 128 eligible patients, 28 (21.9%) experienced frovatriptan inefficacy. In 24 patients with current major depressive disorder, 12 (50.0%) had frovatriptan inefficacy. Only current major depressive disorder was identified as a risk factor for inefficacy (odds ratio = 5.500, 95% confidence interval 2.103–14.382, p = 0.001).
Conclusions
Depression may be a risk factor of frovatriptan inefficacy in patients with migraine, even though half of patients with major depressive disorder respond to frovatriptan.
Introduction
For many patients with migraine, triptans are the best option for acute treatment of a migraine attack (1). However, a meta-analysis reported that 30–40% of patients with migraine do not adequately respond to triptans (1). According to a review of the literature, risk factors for the inefficacy of triptans were the concomitant use of other medications, such as migraine preventives and opioids, the overuse of analgesics, inadequate dosing, previous use of other triptans, the use of the medication late in an attack/baseline severity of pain, incomplete absorption due to gastroparesis or vomiting and pharmacogenetic differences (2). Although several studies reported risk factors, no prospective study has evaluated factors associated with the response of specific triptans.
Frovatriptan is effective in the acute treatment of moderate to severe migraine attack (3). It appears to have a more sustained treatment effect and was better tolerated than almotriptan, rizatriptan and zolmitriptan (3). We examined factors associated with frovatriptan response in patients with migraine.
Methods
Subjects
We invited new patients with migraine who had consecutively visited a headache clinic in the Department of Neurology at Kyungpook National University Hospital since September 2013. The patients were adolescents and adults (aged 18–65 years) who were newly diagnosed at our clinic or already diagnosed but had not taken triptans, preventive medicines or other neuropsychiatric agents within the month. A diagnosis of migraine was assigned based on the International Classification of Headache Disorders, 3rd edition, beta version by a trained neurologist (SP Park) (4). We included patients who experienced at least one attack of migraine per month and who had an attack of at least 6 hours in duration in the preceding 3 months. Patients who had coronary heart disease, cerebrovascular accident or severe hypertension (≥160 of systolic pressure and/or ≥100 of diastolic pressure) were excluded. Patients who had a probable migraine, overuse of headache medication, status migrainosus, may be pregnant, were lactating, or declined to participate in the study were also excluded.
Study design
A prospective, observational study was conducted as part of a hospital-based study that examined the impact of psychiatric disorders on migraine and migraine-associated medications, such as triptans and preventive medicines. The Institutional Review Board of Kyungpook National University Hospital approved the study. All participants gave written informed consent. SP Park interviewed each patient and reviewed the patients’ medical charts to collect demographic and clinical information for a computerized database. Photophobia, phonophobia and osmophobia were defined as hypersensitivity to light, sound and certain odours, respectively, during migraine attacks, which could cause avoidance of those stimulations or aggravation of migraine symptoms. We asked patients whether they had experienced those symptoms in the preceding year. Allodynia was measured using the 12-item Allodynia Symptom Checklist (5) with a cut-off score of >2 defining allodynic patients. Migraine disability was measured by the Migraine Disability Assessment Scale (MIDAS) (6). The overall level of disability was represented as follows: grade I, little or no disability (score of 0–5); grade II, mild disability (6–10); grade III, moderate disability (11–20); grade IV, severe disability (21 or more). Disability of grade I and disability of II were compared to that of grade III and that of grade IV.
At the first visit, the eligible patients were taught to take 2.5 mg of frovatriptan as early as possible after migraine attack. To evaluate the response to frovatriptan, the patients were recommended to keep a diary during a migraine attack, recording whether pain was relieved or absent within 4 hours after the intake of frovatriptan. We selected 4 hours rather than 2 hours as a cut-off time for a response (7) due to the slower onset of the drug’s effect for some patients (3). We defined pain relief as a state when headache pain was changed from being moderate to severe at baseline to mild or none at 4 hours. In the patients who did not respond to an initial trial of frovatriptan, a second trial in the same attack was not permitted. Instead, rescue medications, excluding triptans or ergotamine-containing drugs, were permitted. We assessed frovatriptan to be efficacious when headache responded to its administration in at least one of two successive migraine attacks and inefficacious when headache was not relieved in either attack. When we determined the efficacy of frovatriptan, we finished the observation period. We randomly prescribed preventive medicine, such as propranolol, topiramate or valproate, at the second visit (2 weeks after the first visit) if they had more than four migraine attacks in the preceding month or they experienced significant impairment of work, school or social life due to migraine attack. The maintenance doses of propranolol, topiramate and valproate were 40 mg/day, 50 mg/day and 600 mg/day, respectively. We examined the diary at the second visit and then examined it again 1 month later (the third visit). After that time, the diary was examined every 2 months (the fourth and the fifth visits) until the completion of 5 months of preventive medication. Patients were removed from the study when they had intolerable side effects. We excluded the patients who had no migraine attack or who had only one migraine attack with no response throughout the observation period.
Psychiatric interviews
All participants were interviewed by a neuropsychologist within 2 weeks after the first visit to determine whether they had current major depressive disorder (MDD) or current generalized anxiety disorder using the Korean version of the Mini-International Neuropsychiatric Interview-Plus 5.0.0 (8).
Statistical analyses
The Statistical Package for the Social Sciences (SPSS version 21.0) was used for the data analyses. Descriptive statistics were presented in terms of counts, percentages, means and SD. The independent t test and chi-square test were used to compare continuous and categorical variables as appropriate. Logistic regression analyses were chosen to assess the differential contribution of individual variables to the response of frovatriptan. The results were reported as an odds ratio (OR) with 95% confidence intervals (CI) and corresponding p values. The level of statistical significance was set at p < 0.05.
Results
A total of 246 new patients with migraine consecutively visited our headache clinic. A flow chart illustrated how to include and exclude enrolled subjects (Figure 1). Altogether, 128 patients were involved in the efficacy study. One hundred patients (78.1%) responded to frovatriptan and 28 patients (21.9%) did not. Of patients with response, 92 patients (92%) were pain free within 4 hours and eight patients (8%) felt pain relief within 4 hours. Eighty-two patients (82%) responded to frovatriptan in the first trial and 18 patients (18%) initially responded to it in the second trial. All patients who responded to treatment in the first trial also responded to treatment in the second trial. Demographic, clinical and psychiatric factors except current MDD (p = 0.001) were not different between the patients with efficacy and those without efficacy (Table 1). In 24 patients with MDD, 12 (50.0%) had frovatriptan inefficacy. Previous use of triptans and post-visit preventive medicines did not affect the efficacy of frovatriptan. Using logistic regression analyses, current MDD was identified as a risk factor for frovatriptan inefficacy (OR = 5.500, 95% CI 2.103–14.382, p = 0.001) (Table 2).
Flow chart illustrating the selection of the patients. Demographic, clinical and psychiatric aspects of eligible subjects with regard to the response of frovatriptan. VAS: visual analogue scale; MIDAS: Migraine Disability Assessment Scale; MDD: major depressive disorder; GAD: generalized anxiety disorder. Independent t test or chi-square test. Maximal headache intensity in the preceding month. Factor for frovatriptan inefficacy by logistic regression analyses. OR: odds ratio; CI: confidence interval; MDD: major depressive disorder.
Discussion
Approximately 22% of the patients with migraine had no response to frovatriptan. We reported a lower frequency of triptan inefficacy than that reported in a meta-analysis (1). It may be associated with a different study design. The majority of triptan trials included in that analysis judged the efficacies by a single migraine attack (1). However, we judged them by two successive migraine attacks. It may lessen the possibility to omit patients who did not respond in the initial trial but respond in the second trial and subsequently decrease the frequency of inefficacy.
We found that only depression was a risk factor for frovatriptan inefficacy in patients with migraine. This does not mean that frovatriptan is not worth trying in depressed patients because half of our depressed patients still responded to frovatriptan. However, we believe that the results could provide a meaningful reference for successful therapy with triptans. This study may increase clinicians’ attention to depression in patients with frovatriptan inefficacy. If clinicians acknowledge depression and treat it appropriately, the frequency of inefficacy may be diminished. We look forward to performing a longitudinal study to examine the change of triptan response after the intake of antidepressants in depressed patients.
The reason for the high frequency of triptan inefficacy in depressed patients was not identified. We suggest three possibilities to explain this. First, depression and the response of triptans are likely to share a common mechanism. 5-HT-related gene polymorphisms are known to be related to the pathogenesis of MDD (9) and polymorphism of the 5-HT transporter gene has been reported to be a relevant genetic factor that confers a higher risk of inconsistent response to triptans in patients with migraine (10). The response of triptans in migraine was also associated with catechol-O-methyltransferase gene polymorphism (11), which is associated with MDD (12). Further pharmacogenetic studies are warranted to demonstrate the relationship between depression and the response of triptans. Second, MDD is likely to provoke gastric dysmotility, which impairs triptan absorption. Electrogastrography in MDD patients revealed tachygastria, possibly due to increased sympathetic modulation (13). Tachygastrias have been known to be associated with gastric hypomotility (14). Therefore, we assume that gastric hypomotility and delayed gastric emptying in MDD patients with migraine are likely to affect the response of frovatriptan. A prospective study investigating the therapeutic role of antidepressants in gastric dysmotility in MDD patients with migraine would be interesting. Third, depressed patients are prone to negative cognitions (15). Because pain reporting is subjective, negative cognitions might influence patients’ perception and reporting of pain.
Our study has some limitations. First, the sample size of our study was small. This caused a wide CI, which was compatible with a wide range of possibilities in the logistic analyses. A large population study should be performed to overcome this issue. Second, we did not prove that the impact of depression on the response of frovatriptan also exists for other triptans. We also did not examine the response of other triptans after frovatriptan inefficacy. Therefore, a randomized controlled trial that compares the response of frovatriptan with other triptans and a crossover randomized trial should be conducted in depressed patients with migraine. Third, some patients are likely to respond to frovatriptan after two occasions of unresponsiveness. We did not examine that possibility. A prospective study to clarify the cut-off number of trials in responsiveness should be conducted. Fourth, although we asked the patients to take frovatriptan as soon as possible after migraine attack, it is possible that some patients took it slightly later after the attack than did others. Therefore, we cannot exclude the impact of the time gap between the onset of migraine attack and the intake of frovatriptan on frovatriptan response.
Clinical implications
Approximately 22% of patients with migraine did not respond to frovatriptan with two successive trials. Depression was the sole risk factor for frovatriptan inefficacy. If clinicians acknowledge comorbid depression and treat it appropriately, the frequency of frovatriptan inefficacy may be diminished.
Footnotes
Acknowledgements
The authors thank Ju-Hui Lee, a neuropsychologist, for conducting the MINI-Plus 5.0.0 and helping in the evaluation of the self-report questionnaires.
Declaration of conflicting interests
The authors declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article.
Funding
This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.