In our study, patients showing a favorable response at any time to at least one triptan had a higher probability to be responders to erenumab compared with those not responding to triptans. This information is important as it may improve our understanding of migraine pathophysiology and treatment; it could also be used in clinical practice to advise patients about their chances of response to erenumab treatment. However, previous response to triptans alone should not represent a strict criterion to select patients for erenumab treatment, because many triptan non-responders were erenumab responders.
To our knowledge, this is the first study primarily addressing the association between the response to triptans and that to monoclonal antibodies targeting the CGRP pathway. A previous real-life study found a trend toward better response to erenumab in triptan responders compared with non-responders , being however underpowered to draw definite conclusions. The remaining available real-life studies on the safety and efficacy of erenumab [15,16,17,18,19,20] did not assess triptan response. Notably, the proportion of patients responding to erenumab in our cohort was higher than in randomized clinical trials [12, 21], while it was comparable to other real-life studies [14,15,16]. Our proportion of triptan users was also higher than those of trials [12, 21], while no comparable data are available for real-life studies.
The findings of our study can be explained considering what we know about migraine pathophysiology. A common action on the trigeminovascular system  might explain the association between response to triptans and response to erenumab. A previous study found that patients responding to rizatriptan had higher jugular blood levels of CGRP during migraine episodes compared with patients not responding to rizatriptan; besides, patients responding to rizatriptan had a steep decrease in CGRP after the administration of rizatriptan, which was not found in non-responders . In triptan non-responders, pain neurotransmitters different from CGRP might be important in the generation of migraine; thus, triptan non-responders might be less responsive to CGRP-targeted treatments. It is important to note that while erenumab was designed as a CGRP receptor blocker, the action of triptans on CGRP is indirect.
Our finding of an association between response to triptans and response to a migraine-specific preventative is in line with a previous report which found an association between response to triptans and response to onabotulinumtoxin A . However, the association found by this early study was not confirmed in a further report . The rationale for those studies was that onabotulinumtoxin A acts on the trigeminovascular system as well as triptans . Onabotulinumtoxin A acts on peripheral nerves terminal to interfere with specific events in the synaptic vesicle cycle. These vesicles contain small molecules like acetylcholine and glutamate or vasodilatory neuropeptides including pituitary adenylate cyclase activating peptide 38 (PACAP 38), Substance P, and CGRP. Thus, onabotulinumtoxin A injection inhibits the release of these neuropeptides from primary sensory first order neurons in dorsal root and trigeminal ganglia . During a migraine attack, the headache phase depends on activity in unmyelinated C- and thinly myelinated Aδ-fibers in the dura. Onabotulinumtoxin A appears to selectively inhibit the activation and sensitization of the unmyelinated C but not thinly myelinated Aδ fibers . Preclinical evidence suggests that monoclonal antibodies acting on CGRP inhibits Aδ but not C type neurons in the trigeminal ganglion , therefore having an activity complementary to that of onabotulintoxinA. Taking all the evidence together, monoclonal antibodies acting on the CGRP pathway, triptans, and onabotulinumtoxin A all are involved in inhibition of the release of CGRP, but at the same time they also act on different pathways implicated in the pathogenesis of migraine.
Data about the improvement in response to acute medication are not reported by randomized clinical trials, despite being relevant in clinical practice as an additional efficacy outcome of migraine preventive medication. Improving responsiveness to acute medication is a goal of migraine prevention  and might be an additional parameter to test the efficacy of preventative drugs. In our study, after starting erenumab, more than half of patients reported an improvement in their response to triptans. This favorable effect was appreciated not only in erenumab responders but also in erenumab non-responders; on the contrary, among patients treated with onabotulinumtoxin A only responders reported an improved response to triptans . The improved response to triptans found in patients treated with erenumab can be explained by synergy, as erenumab blocks the CGRP receptor, while the target of triptans is not the CGRP receptor itself. We cannot exclude that the improved response to triptans might also be explained by an overall improved response to acute medication, including triptans and non-steroidal anti-inflammatory drugs, in patients treated with a migraine preventative.
Our data are preliminary and should be taken with caution, as they come from a real-life, non-randomized study. Our study is also limited by a small sample size, allowing reliable univariate comparisons but not multivariate adjustments. The limited number of patients treated with triptans during the three months before erenumab treatment and after starting the treatment also limited the possibility of performing subgroup analyses. Despite the high rate of response to the questionnaire (75%), ensuring the reliability of our sample, the retrospective recall of information through telephone interview is prone to recall bias. Moreover, due to the limited number of patients we could not address differences according to the different triptans. Lastly, our data only refer to patients treated with erenumab, a CGRP receptor antagonist, and are therefore not generalizable to monoclonal antibodies targeting the CGRP molecule.