Network meta-analysis of migraine disorder treatment by NSAIDs and triptans

Migraine is a neurological disorder resulting in large socioeconomic burden affecting approximately 18% of females and 6% of males in the United States [1]. The prevalence of migraine varies with age, females between 35 and 45 years old exhibits the highest prevalence [2]. Apart from the factor of age, the prevalence of migraine in the U.S. also varied with household income and race, and such findings are consistent with studies carried out in other countries [3, 4]. Headache is the primary symptom of migraine and patients may also be afflicted by other symptoms including pulsatile pain, light sensitivity, sound sensitivity, nausea, unilateral pain, blurred vision and emesis. Although a large number of treatments have been developed for migraine over the past decades, several disputes have been encountered by clinicians such as misclassification of migraine, inappropriate selection of treatment and medication overuse. Among them, medication overuse has become a major issue in chronic migraine patients who may eventually develop a disabling condition called medication-overuse headache [5]. Therefore, awareness and understanding of migraine should be improved and corresponding treatments or medications should be further explored to overcome these issues.

Two types of migraine therapies have been developed: preventive therapies which are used to reduce attack frequency or severity and acute therapies which are used for the sake of aborting attacks. Compared to preventive therapies, acute therapies are able to provide patients with rapid and complete relief with minimal or no adverse events and hence they are recommended for promptly alleviating the symptoms of patients [6]. The selection of acute treatments has been differentiated into two pathways: non-specific medications which include analgesics and non-steroidal anti-inflammatory drugs (NSAIDs); and specific medications which include ergot derivatives and triptans [5]. As suggested by the European Federation of Neurological Societies (EFNS), both oral NSAIDs and triptans are recommended for treating migraine attacks [7]. Moreover, evidence from the American Headache Society (AHS) concluded that the following treatments are deemed to be effective acute therapies for migraine: triptans, NSAIDs, ergotamine derivatives, opioids and other combinational medications [8]. Stratified care is a primary strategy often used in selecting medications for migraine patients and this strategy takes several aspects into account: attack severity, the presence of associated symptoms and the degree of disability resulting from migraine [9]. However, other factors such as dosage may also have significant influence on the overall effectiveness of medications that are used to abort migraine attacks.

Among the common acute treatments that are used for aborting migraine, different levels of evidence have been provided by a wide range of studies. Although the efficacy of some medications have been established, this does not imply that such medications should be considered as the first line treatments for migraine patients since it may cause adverse events that are specifically associated with these medications. Despite the growing popularity of triptans, NSAIDs remain one of the most recommended acute migraine treatments and they are often used as an initial strategy for aborting migraine attacks [9]. On the other hand, triptans are often used as a rescue medication if an initial treatment fails to abort migraine attacks and evidence suggests that about 60% of non-responders to NSAIDs can be treated by triptans [10]. One distinctive advantage of triptans for migraine patients is that they can be effective at any time during a migraine attack and such an advantage may reduce the impact of dosage timing on the overall efficacy. Moreover, some evidence suggests that earlier intervention by using triptans is associated with an enhanced efficacy [11, 12], while some randomized trials do not support such an improved efficacy when patients experienced allodynia in the course of a migraine attack [13, 14].

Despite the fact that both NSAIDs and triptans have been recommended by the EFNS and AHS as acute treatments for migraine, comparing NSAIDs with triptans is a challenging task. Conventional meta-analysis has several limitations due to the lack of evidence as well as lack of indirect evidence.. For this reason, we designed this network meta-analysis (NMA) to compares the relative efficacy and tolerability between NSAIDs and triptans. We hope that the approach of NMA can provide comprehensive evidence with respect to the efficacy and tolerability of these two popular medications.

In this NMA, 10 medications were included and the result reveals that eletriptan offers the best efficacy and acceptable tolerability. Besides, our research indicates that ibuprofen exhibited the most desirable tolerability. Furthermore, diclofenac-potassium and sumatriptan-naproxen also showed favorable properties concerning efficacy and tolerability.

Triptans were a group of 5-HT_1B/1D agonists [102], three main mechanisms of them were all conduced to anti-migraine function. Firstly, triptans attenuated the release of vasoactive peptides trigeminal system, as well as reduced the migraine vascular inflammation. Moreover, triptans were shown to potentially inhibit the nociceptive pathway of central sensitization, thus helped to relieve the pain from migraine [103, 104].

Considering the primary efficacy end-point, triptans perform equally well compared to NSAIDs though eletriptan has the best efficacy, which lends credence to the findings of Chris Cameron et al.’s 2015 study in principle [105]. However, this study did not take adverse events into account. Therefore, we apply 4 adverse-events to characterize this ability in all 10 medications. Additionally we also included a double-component therapy. Here we report this NMA, revealing both the efficacy and the tolerability of present medication against migraine.

At first, we focused on the differences apparent in the primary efficacy end-point between different types of medications. Rizatriptan provides relatively good freedom from pain and nausea though with poor pain relief, the reason for that might be the different criteria for efficacy in each study. When it comes to tolerability, NASIDs seem to be more attractive solutions. Also, it is of significance that this study found naproxen is capable of significantly improving the tolerability of sumatriptan and has no influence on its efficacy.

As suggested by the rank probability of SUCRA, eletriptan exhibited the most considerable efficacy. From the SUCRA data, it is obvious that eletriptan can reduce pain with a better result than any other medication. In the meantime it also performs better than most of others in 1 h pain-free and 2 h pain-free. Eletriptan is a new 5-HT_1B/1D/1F-selective receptor agonist with a higher affinity to the receptors when compared with other triptans [106]. Besides, more rapid and consistent absorption has been achieved through structural design, and this has made it possible for the drug to pass through the blood-brain barrier [107]. As a result of its enhanced hydrophobility, higher bioavailability and longer plasma half-life have also been reported [108]. When compared with sumatriptan and other triptans, the difference in efficacy may be explained by the overcoming of the blood-brain barrier, which leads to a faster and more consistent absorption [107].

When we turn attention to the NSAIDs, ibuprofen attracted us by its superior tolerability amongst all observed medications. Though ibuprofen has been available as a non-prescription medication for more than 40 years, the mechanism of how the drug works is still not completely understood. According to a widely accepted theory, it may be related to prostaglandin synthetase inhibition, therefore allowing better tolerability. From the SUCRA data we can observe that ibuprofen ranked top three in all the adverse-event indications.

The results of SUCRA also showed that the diclopenac potassium performs with high efficacy and tolerability, in fact it stood the best option among NSAIDs from a comprehensive point of view. At the mechanism level, NSAIDs inhibit the activity of cyclooxygenase (COX), which is recognized as being composed of two isoforms (COX-1& COX-2). COX acts as a catalyst during the production for prostaglandins, a substance responsible for pain and inflammation. Diclofenac inhibit both COX isoforms, though with a lower activity for COX-2 [109, 110].

Meanwhile we recognized that sumatriptan-naproxen also offered a high-level tolerability, ranking first in rescue medication and recurrence and fourth in the other two indications among the ten medications. The addition of naproxen significantly improved the tolerability of sumatriptan. To understand the reason for this we referred to the mechanism of both the medicines and the migraine.

The pathophysiology mechanism of migraine is quite complex, involving multiple neural pathways that appear to be pivotal during the process [111]. In the early stage of a migraine, vasoactive and substances including calcitonin gene-related peptide and kinins are released by trigeminal nerve endings under the stimulation of cortical spreading depression. At the same time, the central pathways’ activation depends on the signals of pain from the periphery. However, in the later stage, central sensitization has no relationship with peripheral neural input [112].

Considering the multiple pathogenic mechanisms, multi-mechanism-targeted therapy may have better effect than monotherapy. Triptans not only decrease transmission of the pain impulses to the trigeminal nucleus caudalis but also release inflammatory mediators from trigeminal nerves, therefore reduce calcitonin gene-related peptide-mediated vasodilation [113]. As for naproxen, it suppressed sensitization of central trigeminovascular neurons in the spinal trigeminal nucleus [20]. In our study, the combination of sumatriptan and naproxen effectively altered peripheral activation of central pathways during early period and development of central sensitization during later periods. As a result, a high-level tolerability was observed, and this possibility was supported by several clinical studies [114‐116].

What attracted our attention most is the potentiality to combine different medications together and make use of the advantages of each considering the relevant stage. Applying different medications to intervene at every key point of the multiple pathogenic mechanisms may bring us closer to a better outcome. For instance, we may combine naproxen with eletriptan to attain treatments with both optimal efficacy and tolerability.

As with all analyses, we still cannot avoid several limitations. First, age and gender was not under consideration. Further research is needed in assessing the efficacy for different groups of people. Second, long-term assessment is also important. As we all know, people who suffer from migraine may undergo a long-period treatment and therefore the efficacy and safety of medications are vital. Third, the dosage of medications was not considered and that may cause some deviations.