The introduction of triptan medication has broadened the spectrum of potential migraine treatments, offering a greater array of options for clinicians and patients alike. In addition to evaluating the efficacy of these drugs, it is imperative to ensure their safety. This study explored the risk status of its AEs from the perspective of signalling risk by accessing triptan data from the FAERS database and performing signal mining. By undertaking a comparative and analytical examination of the AEs of sumatriptan, zolmitriptan, rizatriptan, and naratriptan as reported in the FAERS database, this study offers a comprehensive understanding of the similarities and differences in the safety profiles of these four drugs in common, novel, and rare AEs. In clinical practice, AEs associated with triptans affect multiple organ systems, including the neurological, gastrointestinal, and cardiac systems. Our data mining process identified all of the AEs listed in the drug’s package insert. The four drugs share an AE, which is Reversible cerebral vasoconstriction syndrome.

The initial triptan developed by GlaxoSmithKline ® and introduced to the market in 1991 was sumatriptan (GR43175). While it demonstrated efficacy in the acute treatment of migraine, particularly when administered parenterally, the low oral bioavailability of sumatriptan prompted the development of a second generation of triptans [28]. In the present study, the highest number of AEs was reported for the first generation of sumatriptan. This may be attributed to the fact that it is the earliest triptans to be introduced on the market and therefore more widely used in clinical practice. With regard to age and gender, the data revealed a higher incidence of AEs in female patients. This finding may be attributable to the elevated prevalence of migraine in women, which may result in a greater utilization of triptans in women in clinical practice. This finding indicates that, in the future development of new drugs, consideration could be given to the creation of a new generation of drugs for different genders and age groups. For example, a formulation of the triptans class specifically targeting premenstrual migraine in women could be developed and could be combined with the mechanism of action of non-steroidal anti-inflammatory drugs (NSAIDs) with a view to reducing the incidence of associated AEs.

In the course of our study, AEs associated with triptans were observed to affect multiple organ systems, including the nervous system and the heart, in actual clinical practice. In the context of cardiac disorders and cardiovascular disease AEs, clinical trials and drug inserts for triptans indicate that the use of this medication is contraindicated in patients with risk factors for cardiovascular disease and the cardiac system. These risk factors include, but are not limited to, the following: ischemic coronary artery disease (e.g., angina pectoris, history of myocardial infarction) and a history of stroke or transient ischemic attack [29,30,31]. Our study also confirms that sumatriptan may lead to adverse events such as Coronary artery dissection (n = 37), Angina pectoris (n = 18), Arteriospasm coronary (n = 13), rizatriptan may lead to Myocardial infarction (n = 5) and zolmitriptan may lead to Palpitations (n = 4). The aforementioned data collectively indicate the presence of a potential risk factor for cardiac disease in the context of triptans utilized in actual clinical practice. Triptan has vasoconstrictive properties and exerts its pharmacological effects mainly by acting on the 5-HT receptor. The affinity for different subtypes of 5-HT receptors varies among the different triptan analogues. In the cerebral vasculature, some triptans selectively constrict dilated intracranial blood vessels, thereby relieving migraine symptoms. However, in the peripheral vasculature, such as the coronary arteries, their effects are more complex [10, 32, 33]. Clinical trials and research reports have identified the potential effects of triptan on cardiac function. In a small number of cases, cardiovascular ischaemic events ( myocardial infarction, cerebral vasoconstriction ), as well as other symptoms including palpitations and arrhythmias, have been reported. However, the incidence of these events is relatively low [34,35,36,37]. It has been postulated that Tretinoin may also induce related cardiac adverse effects via its influence on neurotransmitter release and vascular endothelial function, among other mechanisms. Further investigation is required to elucidate the precise mechanism of action. The data presented herein underscore the potential risks associated with triptans in individuals with pre-existing cardiac disorders. Consequently, it is imperative that future drug development prioritise the creation of more selective and relevant analogues, with the aim of reducing vascular-related AEs.

Given the expression of 5-HT1B and 5-HT1D receptors in multiple regions of the central nervous system (CNS), it is reasonable to hypothesise that triptan may induce adverse central effects, which may depend on lipid solubility [38]. The present study identified nervous system disorders as the primary SOC category for four drugs in the FAERS database. Additionally, it was determined that the AE “reversible cerebral vasoconstriction syndrome,” which is common to all four drugs, also belongs to the Nervous system disorders category. It is hypothesised that the lipid solubility of some triptans and the disruption of the blood-brain barrier during a migraine attack may facilitate the penetration of anti-migraine drugs into the CNS [39, 40]. It is particularly important in the future to update the new generation of tretinoin based on pharmacological mechanisms. A further avenue for investigation is the potential rational adjustment of the lipid solubility of the new generation of triptans, without compromising their pharmacological efficacy or pharmacokinetics, or whether 5-HT should be highly selected for the treatment of migraine through targeting.

We also observed that the first 30 most frequent and highest signal intensity detections for all four drugs involved gastrointestinal disorders. The AEs with the highest frequency associated with zolmitriptan, rizatriptan, and naratriptan medications are all classified as gastrointestinal disorders. It has been reported that triptans may cause gastrointestinal complications, including ischemic colitis, a finding that was also confirmed in our study [41]. Respiratory, thoracic and mediastinal disorders ( dyspnoea, chest pain, etc.) had the first frequency of sumatriptan, which is consistent with AE reports from previous studies [40]. AEs for gastrointestinal disorders are a common occurrence in a diverse range of pharmaceutical agents employed for the management of pain, including NSAIDs such as ibuprofen and acetylsalicylic acid, as well as opioids [42, 43]. In clinical practice, a significant proportion of patients express concern that oral medications may cause damage to the gastrointestinal tract, which can lead to AEs such as nausea and vomiting. In the case of triptans for migraine, AEs on the gastrointestinal system have also been observed, which provides a valuable reference point for clinical use. It may be advisable for patients with digestive disorders to be administered drugs with a lesser propensity for side effects or the early development of new dosage forms that do not need to be absorbed through the gastrointestinal tract.

The results of a recent meta-analysis have demonstrated that four of the tretinoin analogues (sumatriptan, zolmitriptan, rizatriptan, and eletriptan) are more efficacious in the treatment of migraines than the recently marketed and more expensive drugs lasmiditan, rimegepant and ubrogepant. Consequently, these four tretinoin analogues should be considered as the drugs of choice for the treatment of migraines [44]. Previous studies have explored the adverse effects associated with gepants, which are used for the prophylactic and acute treatment of migraine, and which have a different mechanism of action than triptans. Researchers have also identified AEs related to the gastrointestinal system and have shown that it is more suitable for patients with a history of cardiovascular disease compared to triptans cardiovascular side effect risk, however comparative and real-world studies between triptans in recent years remain unexplored [45]. The safety and efficacy of migraine treatment are contingent upon the characteristics of the drug in question, as well as the patient’s specific circumstances, including the use of multiple medications. Consequently, further investigation into the adverse effects associated with the triptans is currently a priority. Our study addresses a current gap in the literature by analysing AE signals at multiple levels. The findings can be used to inform treatment choices and facilitate informed decision-making between patients and clinicians. Future research should focus on a detailed characterisation of the specific mechanisms of action of 5-HT receptors in migraine and other related pain conditions. Additionally, efforts should be made to minimise potential side effects in response to current real-world adverse effects, and the development of more specific drugs to optimise migraine treatment strategies by precisely targeting therapy should be a priority.