Migraine is one of the most common neurological diseases, affecting more than 1100 million people worldwide [1]. Migraine is the most common type of headache after tension headache, but it has the highest morbidity and disability rates [2, 3, 4]. The prevalence of migraine is 14.0% globally [5], 17.0% in Latin America [5], and 19.6% in Colombia [6]. The acute management of migraine involves simple analgesics such as nonsteroidal anti-inflammatory drugs (NSAIDs) or acetaminophen and specific medications such as triptans [4, 7, 8]. However, a significant proportion of people require prophylactic interventions with $\beta$-blockers and antiepileptic drugs, among others, due to very frequent headache attacks or the inability to control headache with acute pharmacological therapy [4, 7, 8].

The frequent use of medications to treat acute headaches can lead to an increase in the frequency of pain episodes and a transition from episodic headache to chronic headache [9, 10, 11]. Medication-overuse headache (MOH) is a chronic type of headache that is associated with the excessive use of medications such as triptans, ergot derivatives, NSAIDs, acetaminophen, or opioids [9, 10, 11, 12]. There are more than 58.5 million people with MOH worldwide [3]. MOH can involve any type of headache, but the most common type involves the chronicity and transformation of migraine [13]. Compared with other analgesic therapies, the excessive use of triptans causes MOH to develop more quickly [13].

The negative impact of MOH on the quality of life of affected individuals is greater than that of episodic migraine, as is the cost of care for MOH [9, 13]. The excessive or inappropriate use of analgesics in individuals with headache attacks is one of the most important modifiable risk factors [11, 14]. Therefore, it is crucial to prevent the development of MOH by identifying patients who are at greater risk, such as those who have excessive dispensings of antimigraine drugs, such as triptans [13]. Furthermore, the prevalence of MOH in patients receiving triptans ranges from 2.1% to 46.3% [15].

The Colombian healthcare system provides coverage to the entire population through two main regimes (contributory and subsidized regimes). All employees, pensioners, and self-employed workers must be enrolled in the contributory regime. Coverage for individuals who are unable to pay is provided by the subsidized regime, which is financed by the state. The health benefits plan is the same for both regimes and includes some triptans in different pharmaceutical forms for the management of migraine attacks [16]. In Colombia, some pharmaco-epidemiological studies have been carried out in patients with migraine, but there are no reports that address the excessive dispensing of triptans [17, 18, 19]. The objective of this study was to determine the use profile and safety of triptans in a group of patients with migraine who had excessive dispensings of antimigraine drugs in Colombia.

Between July and September 2023, 9147 patients were identified as having been dispensed triptans. Among these patients, 44.6% (n = 4083) were considered to have excessive dispensings (Fig. 1). Supplementary Table 2 compares participants (n = 355) with non-participants (n = 2424). Overall, the groups were similar across most variables. Participants were slightly younger (median 40.0 vs. 42.0 years) and differed in the distribution of some geographic regions and health insurance categories. No significant differences were observed in sex distribution and triptan type.

In this study, we investigated the sociodemographic and clinical characteristics of patients with migraine who received excessive dispensings of triptans, as well as the use of these medications, the most common adverse reactions, and the factors related to MOH. A total of 8.2% of the patients developed MOH, and several factors were associated with a higher probability of its occurrence, including older age, longer disease duration, prior use of analgesics, and the presence of psychiatric comorbidities. The World Health Organization announced that the inappropriate use of drugs is common worldwide. In addition, the excessive or improper use of drugs leads to wasted resources and widespread health risks [24]. By understanding how medications are used in the real world, strategies to improve physicians’ prescribing habits can be designed to increase medication efficacy and safety [25].

In this sample of patients with migraine, women and young adults predominated, as reported in other studies [15, 17, 19, 26, 27, 28, 29, 30, 31, 32, 33]. Similarly, migraine without aura prevailed, and the attacks were usually severe, which is consistent with the literature [26, 27, 28, 32]. Sumatriptan was the most commonly prescribed triptan, which is consistent with previous reports in the country [18, 19]. Zolmitriptan was previously found to predominate in Denmark and the Netherlands (52.0%–74.8%) [31, 34], while zolmitriptan predominated in Australia and France (32.5%–42.6%) [33, 35], and rizatriptan predominated in Japan (33.6%) [30]. These differences in drug use patterns may be due to various reasons, including the availability of drugs in each country, health system coverage, doctors’ medication use habits, academic training, and the clinical response to triptans [18, 19, 30, 31, 33, 34, 35]. With respect to effectiveness, half of the patients were always or almost always pain free within 24 hours of medication intake, which is consistent with the findings of a systematic review and meta-analysis of clinical trials [36]. Gepants are recommended for patients who do not respond satisfactorily to triptan therapy [37, 38]. They are effective and well tolerated, with a minimal risk of MOH [37, 38]. However, at the time the study was conducted (2023), these medications were not available in Colombia [16].

Among the triptan users, 44.6% had excessive dispensings, which is consistent with findings reported in Italy (43.3%) [32] and higher than those reported in other European countries (2.3%–21.5%) [31, 34, 35], Australia (6.0%) [33], and Japan (3.7%) [30]. Find et al. [39] conducted a multicenter study across several European countries (Denmark, Germany, Italy, and Spain) and two Latin American countries (Argentina and Chile), reporting that excessive triptan use was substantially more common in Europe than in Latin America (30.8% vs. 5.6%, respectively). However, the methodology of these investigations was different from that proposed in this report, so these findings may not be fully comparable [30, 31, 32, 33, 34, 35, 39]. Additionally, 22.8% of the patients used unapproved doses of triptans [20, 40]. The correct way to use triptans is by administering an initial dose at the time of the migraine attack, which can be repeated after 2 hours if there is no improvement in pain [20, 40]. Surprisingly, some patients used these drugs on a daily basis. These findings are consistent with those reported in a Colombian study that included patients with migraine who were treated with ergotamine [17]. The study revealed 26 different dosages, of which 99.5% were inappropriate; in 34.6% of the patients, ergotamine was used for indications that were not approved by regulatory agencies [17].

The adverse events that were documented in this investigation are consistent with those reported in other studies [20, 26, 40]. According to a meta-analysis of clinical trials, triptans were associated with a greater probability of adverse events than placebo or other pain relievers, such as acetaminophen and NSAIDs [26]. The risk increased when these drugs were used at high doses [26]. In addition, 8.2% of the patients experienced MOH, which is in line with a systematic review that included 20 studies conducted in Europe, North America, and Asia [15]. The prevalence of MOH among patients who received triptans ranged between 2.1% and 46.3% [15]. It is essential to limit the frequency of acute analgesic use to prevent MOH, as outlined in clinical guidelines, which recommend restricting triptan use to no more than nine days per month [10, 41]. Several strategies can be implemented to control excessive drug dispensing, such as controlling the number of units allowed per drug from health insurers, health providers, or pharmaceutical managers. The use of electronic drug management systems would allow alerts to be issued when physicians enter medication orders with excessively high quantities, enabling the physician to adjust the treatment regimen in a timely manner [42]. The use of electronic health systems reduces errors and increases patient safety [42, 43].

According to the literature, the frequent use of analgesics is a risk factor for the development of MOH [9, 10, 12, 14]. This finding is consistent with the previous use of other pain relievers in this study. It is important to implement continuing education programs on the correct use and dosage of medications that can improve the clinical practice of physicians [25, 44]. Migraine prophylaxis was also associated with a higher probability of MOH, which is similar to the Chronic Migraine Epidemiology and Outcomes (CaMEO) Study conducted in the United States [28]. However, this association should be interpreted with caution, as the cross-sectional design does not allow for causal inference. The finding may reflect confounding by indication: patients with more severe, frequent, or disabling migraine are more likely to be prescribed prophylactic therapy, and these same clinical characteristics also increase the likelihood of frequent use of abortive medication, thereby raising the risk of MOH [4, 7, 8]. Consequently, the observed association may reflect the underlying severity of the disorder rather than a true treatment effect. In addition, the presence of psychiatric comorbidities also increased the risk of MOH, which is consistent with other reports [27, 28, 29]. The dysfunction of neurotransmitters present in individuals with anxiety and depression disorders may play an important role in the development of MOH [11]. Other factors that increase risk, such as increased body mass index, smoking, admission to the emergency room in the last 6 months, severe migraine, and pain intensity, are mentioned in the literature [11, 27, 28, 29]; however, these factors were not found or were not evaluated in this study.

When interpreting the results, several limitations must be considered. First, the data were obtained from a group of patients insured by the Colombian health system, so the findings cannot be extrapolated to patients who do not have insurance. Second, although some differences were observed between participants and non-participants, the overall distribution of key variables was comparable, indicating that non-response or selection bias is unlikely to meaningfully influence the study’s conclusions. Third, the drug dispensing database does not allow the identification of drugs that patients may have purchased with their own resources. It also lacks information on complementary studies (e.g., neuroimaging studies), and it also does not allow differentiation between dispensing and medication intake. Fourth, recall biases may have occurred (e.g., in data on efficacy or adverse events) because the information was obtained by telephone. However, the calls were made the month after the dispensing. Fifth, a causal relationship between patient-reported adverse events and the use of triptans was not established, so it is possible that adverse events could be secondary to the use of other medications or be symptoms secondary to migraine. Sixth, the cross-sectional design of the study precludes the establishment of causality or the assessment of the temporal sequence between exposure and outcome. Because both variables are measured at a single point in time, it is not possible to determine whether the exposure preceded the outcome or whether the outcome may have influenced the exposure. Consequently, the findings should be interpreted strictly as statistical associations rather than causal relationships. However, the study included a significant number of people distributed across different geographic regions of Colombia, involving both men and women of different age ranges who were affiliated with the country’s health system.

Based on these findings, we conclude that excessive dispensing of triptans is common among migraine patients included in this study, predominantly women, with a mean age of 40.9 years and a disease duration of 11 years. These patients frequently present high blood pressure, anxiety disorders, and irritable bowel syndrome. In a considerable proportion of patients, the dosage does not correspond to the recommendation given by the clinical practice guidelines. More than 41% of the patients experienced adverse events, and 23% had to suspend treatment for this reason. Increasing age, history of migraine $\ge$10 years, previous use of simple analgesics, and the presence of concomitant psychiatric disorders were associated with a higher probability of MOH. However, these findings reflect only the prescriptions captured in our database and may not fully represent the use of over-the-counter triptans. Continuing education programs should be implemented, and more electronic drug management systems should be used to improve patient safety.

The daata used in this study are available on protocols (DOI: https://www.protocols.io/private/A2C3FF6834AB11EFA81B0A58A9FEAC02).

LFVR, CDA, LFNS, MJSP, JMZO, and GVA participated in the drafting, data collection, data analysis, and description of the results and discussion. JEMA participated in the drafting, data collection, data analysis, description of results, discussion, critical revision of the article, and evaluation of the final version of the manuscript. All authors read and approved the final manuscript. All authors have participated sufficiently in the work and agreed to be accountable for all aspects of the work.

The protocol was approved by the Bioethics Committee of the Technological University of Pereira and classified as risk-free research (approval code: 22-270223). The ethical principles established by the Declaration of Helsinki were followed. Verbal informed consent was obtained prior to telephone interviews for selected patients aged $\ge$18 years. The Ethics Committee approved the use of verbal informed consent. Telephone numbers were used solely for contacting participants and were not incorporated into the analytical dataset. No names or other personal identifiable information were recorded at any stage of data collection.

We thank Ximena Andrea Córdoba Castro for her work in obtaining the database.

This research received no external funding.

LFVR, JEMA, CDA and JMZO work for Audifarma SA, without implying any commitment to the brands of medicines that are dispensed. The other authors have not any conflict of interest.

Supplementary material associated with this article can be found, in the online version, at https://doi.org/10.31083/RN46355.