In this study, we evaluated if the non-use of triptans was justified by the presence of contraindications or prior adverse events. We analyzed if triptan naïve patients had a higher frequency of vascular risk factors associated with stroke or cardiovascular conditions. Finally, we analyzed differences in clinical situation and previous management between the groups of triptan users and triptan naïve patients. We specifically studied CM patients because in that population, there is no doubt on the need of a triptan prescription3,4.
The main results of our study were that the percentage of triptan naïve patients was surprisingly high (74%), that the frequency of formal contraindications was sparse (3%), that the percentage of patients that discontinued triptans because of adverse events low (12%), and that the non-use of triptans was associated with a worse clinical situation and worse previous management, indicated by a higher frequency of acute medication use, a higher frequency of MOH and a lesser prior use of prophylactic drugs.
Headache disorders are the second cause of years lived with disability worldwide23. CM patients are frequently underdiagnosed and undertreated, not only in primary care, but also at the specialized level13. Only 40.8% of CM patients have a consultation with a healthcare professional for headaches, and 4.5% receive adequate diagnosis and treatment24.
The main options in the acute treatment of migraine attacks are NSAIDs, ergots and triptans25, although recently ditans and gepants have been used26,27. Although NSAIDs are the most widely used treatment in migraine attacks28, triptans are more migraine specific and its efficacy rate is overall higher than NSAIDs or ergots29,30. In our sample, only a fourth of all CM patients were under triptan use. National studies conducted in Spain showed a frequency of use of 17%-48%14,15, compared to 14 to 25% in other countries 13, 31. It is also surprising that opioids, which are not specific migraine treatments and have more frequent and serious adverse effects, are frequently used in migraine32, showing that opioidophobia seems uncommon.
Triptans are 5-hydroxytriptamine (5-HT) agonists with several mechanisms of action. First, they decrease the diameters of systemic and intracranial arteries, by 5-HT1B receptor stimulation33. Second, they inhibit axonal transmission acting on trigeminal 5-HT1B and 5-HT1D receptors33. Third, they might diminish neurogenic inflammation, targeting presynaptic 5-HT1B, 5-HT1D and 5-HT1F receptors, decreasing Calcitonin Gene-related Peptide (CGRP) and Substance P34.
Adverse events of triptans are related with their effect on 5-HT1B receptors35, being contraindicated in subjects with coronary artery disease, coronary vasospasm, prior cerebrovascular events, peripheral arteriopathy or uncontrolled hypertension7. Despite its potential risks, serious cardiovascular effects occur in < 1/1.000.000 exposures, the most severe events being stroke and myocardial infarction36,12. In our sample, only a minority of patients without triptan use presented contraindications (3.2%), so contraindications seem insufficient to explain the non-use of triptans.
The main vascular risk factors associated with both stroke and ischemic coronary disease are hypertension, hyperlipidemia, diabetes, smoking or obesity37. Therefore, we analyzed if the non-use of triptans could be associated with an excessive concern for vascular events. Nonetheless, frequency of vascular risk factors was similar between the two groups, without significant differences. Evidence suggests that migraine patients have increased vascular risk38, and especially those with aura, those who smoke, those treated with contraceptives, and those older than 40 years old21. Therefore, some authors do not recommend triptans in old patients39. Nevertheless, we could not find differences in age, use of oral contraceptives, or seniority.
Triptan non-use was not justified by a worse efficacy compared with NSAIDs or ergots, presence of contraindications, or an increased frequency of vascular risk factors. Two other explanations seem possible: a worse tolerability profile or treatment expense. Concerning tolerability, frequency of adverse is estimated around 17–41% in ergots40, 5–28% in NSAIDs and 40% in triptans7. In our sample, adverse events led to triptan discontinuation in 12% of patients. Adverse event profiles differ: NSAIDs typically cause gastrointestinal AE11, and ergot derivatives cause nausea or vomiting41. The most frequent triptan AE are nausea (10%), dizziness (4%), fatigue (3%) and feeling of heaviness (3%)11.
Triptans can cost between 4 and 62 times higher than NSAIDs. Still, the Spanish healthcare system covers between 0%-60% of the total price42. Retired workers with less than 18.000 € of annual income only contribute a 10% of the total cost, with a maximum amount of 8.23 € per month42. The total annual cost of CM is estimated to be 12,922 € per patient. Only 43% corresponds to the direct cost15. Despite the higher cost of triptans, they have proven to be cost-effective, due to the decrease of direct costs related with emergency department6 consultations and indirect costs13,43. Therefore, neither tolerability nor cost seem to fully explain the underutilization of triptans.
All CM patients should be under prophylactic medication44. In our sample, only 51% of the patients were under preventive treatment, in line with comparable series (49%)15 and more than primary care-based series (1.6–14%)13. One of the most remarkable findings of our study was the significant difference of prior prophylactic treatment in patients treated with triptans compared with triptan naïve subjects, being almost twice as frequent (79% vs. 35%).
We examined whether differences in triptan use were related with a delayed referral to Headache specialized care. In our setting, general practitioners can refer patients directly to our Headache Unit without prior consultation with a general neurologist, reducing the wait time. In our sample, we could not explain differences in time prior to the referral by the use or non-use of triptans, being 36 and 38 months in both groups.
We used the term triptanophobia to define the excessive and inadequately justified concern of health professionals about the potential risks of triptans. It should not be interpreted in a pejorative or dismissive way. The reasons for the non-use of triptans seem multifactorial; however, in the present study we observed that the relative weight of many of them seem insufficient, so there must be some degree of triptanophobia.
Causes of triptanophobia can be related to education on headache medicine. Headache education is not an obligatory rotation during neurology residence curriculum. The lower percentage of preventive use in triptan naïve patients may also suggest this worse management of CM patients. It could also be motivated by the atypical commercial presentation, in blisters of two to nine pills, unlikely for a medication that should be used frequently.
Our study had several limitations: it is a single-center study with an unusual referral pathway. In some patients, there could exist some degree of memory bias, but we reviewed referral charts and double-checked prescription history in every case. The study could fail to detect differences in the frequency of vascular risk factors, given that the sample was not sized primarily for that, but all the relative frequencies were similar with the sole exception of hypertension (4.9 vs 7.6%). Prior use of preventive medications could also influence the results, but all included patients met CM criteria when included, suggesting that almost all preventive drugs failed in them. Triptanophobia is a new term that may not fully correspond to the classic definition of phobia. We use this concept in a practical way to try to explain the underutilization of triptans, without assuming the negative connotations of phobia. Among the strengths of our study, we analyzed an important subject not previously studied in detail. Our study design allowed us to study multiple effects and multiple exposures, given the high prevalence of migraines. The large sample size also gave robustness to the analysis. Patients were diagnosed in an experienced setting and quality of information was high. More research on this subject is needed to definitely demonstrate some of this hypothesis. Future studies should analyze the presence of triptanophobia in larger samples and different settings, specifically analyzing if triptan use might change the clinical situation.