Author response to ‘Clarification on the incidence and sex-specificity of sexual dysfunction as an adverse event of CGRP-targeting medications’

We would like to thank Dr Do for the comments raised in the Letter to the Editor (1) in response to our recently published case reports concerning sexual dysfunction in two female migraine patients as a potential side effect of CGRP(-receptor) targeted drugs (2). While we appreciate and encourage the ongoing discussion in the field, we believe that several aspects of this potential side effect, as well as the overall message of our paper, were misinterpreted by Dr Do.

Firstly, Dr Do mentioned that ‘any adverse event, especially one impacting sexual health, necessitates thorough investigation’. This statement is supported by data from the US Food and Drug Administration Adverse Event Reporting System (FAERS), indicating a small number of five cases of sexual dysfunction in females, primarily associated with the use of erenumab, fremanezumab, and galcanezumab. We acknowledge that these data show that such cases might be rare, and by no means have we claimed that the prevalence is expected to be high in these drug users. However, these numbers should be placed into the proper context, considering i) the recent approval of these medications, the relatively limited clinical experience in prescribing them, and an expected growing number of users, and ii) the global problem of stigmatization and underreporting of adverse events by clinicians in general (3,4) – as mentioned in the Letter – but also other healthcare professionals including pharmacists (5), and importantly, the undervalued role of patients in pharmacovigilance (6).

We believe that the latter problem of underreporting plays a significant role in these specific cases. Indeed, both migraine and sexual dysfunction are surrounded by (social) stigma (7,8), which is often insufficiently recognized. Migraine-related stigma is further associated with more disability, greater interictal burden, and is – like sexual dysfunction – linked to reduced quality of life (9,10). (Self-)stigma on sexual health problems is also further complicated by mental health problems and associated with socio-economic status (11). While several studies indicate barriers to communicating sexual health among healthcare professionals treating patients with chronic illnesses, further influenced by, e.g., discomfort and socio-cultural norms and values (12), it is noteworthy that such barriers might even be more prominently present among neurologists treating migraine patients primarily for headaches. Discussing a topic such as sexual dysfunction, especially when CGRP(-receptor) targeted drugs are actually proving effective for treating migraine attacks, might feel inappropriate or embarrassing. Yet, suffering from such side effects might be a valid reason to stop or switch to another CGRP(-receptor) targeted drug – as was the case in the first patient described in our paper (2). While we do not advocate that this topic should primarily be discussed during every consultation with patients, we believe that the low incidence numbers mentioned by Dr Do only further emphasize the importance of recognizing this potential adverse event, taking it seriously, and acknowledging its impact on this patient population. A referral to a gynecologist, sexologist or simply addressing the patient's concerns could already lead to a substantial improvement in the patient's quality of life. Educating and empowering patients to address such potential side effects is also crucial herein (8).

Secondly, Dr Do mentions the complexities surrounding sexual dysfunction as a multifactorial condition influenced by several diseases that are comorbid with migraine, including depression and anxiety (1). We appreciate this critical observation, which we have addressed by explicitly noting that the first patient was not diagnosed with any psychiatric condition (2). Additionally, it was unlikely that depressive manifestations were present in the second patient, as these had subsided following the cessation of hormonal contraceptives decades earlier (2). We also admit that the causality assessment is not (yet) optimal in both patients, as they do not (yet) fulfill two critical criteria for defining sexual dysfunction as a drug-related adverse reaction, i.e., dechallenge associated with disappearance and rechallenge associated with the reappearance of the adverse event. However, completely fulfilling the definitions is practically and ethically challenging. Additionally, these limitations should not hamper vigilance on these complaints – which, considering the timeline, seemed to be primarily linked to the use of CGRP(-receptor) targeted drugs. Detailed reporting during a more extended follow-up period by, again, collecting and publishing more cases could eventually result in sufficient power to draw causal conclusions on the association between the use of these therapies and sexual dysfunction - requiring adequate adjustments for confounders. Of note, whether it is justified to adjust for diseases comorbid with migraine, such as anxiety and depression, can be debated and might depend on the specific type of CGRP(-receptor) targeted drug or comorbid disease. Indeed, if these diseases are thought to be confounders, each of them must be a cause of the outcome (i.e., sexual dysfunction) and a cause of the exposure of interest (i.e., CGRP(-receptor) targeted drugs) (13). As an example, depression has been causally linked with migraine (14), and more importantly, anti-CGRP(-receptor) monoclonal antibodies have been shown to improve depressive symptoms in individuals with migraine – independent of a reduction of migraine (15). However, such effects were observed for erenumab, but were less evident for fremanezumab (15,16) – highlighting the need for future clinical studies to understand such differences in clinical responses, and potentially, adverse events, between different antimigraine drugs targeting CGRP or its receptor (17). In addition, further basic studies are warranted to either confirm or refute the pathophysiological hypotheses regarding peripheral blockade by monoclonal antibodies, particularly in the vagina and clitoris, as raised in our paper (2).

Third, substantiated by the presented number of reports extracted from the FAERS, Dr Do mentions that sexual dysfunction is a rare side effect that is not sex-specific (1), considering its presence in both sexes. This observation has already been extensively elaborated on in our paper, and we definitely do not claim it is specific to females only. We have indeed previously published the male counterpart to these case reports, describing a 54-year-old male migraine patient using galcanezumab who reported erectile dysfunction and whose potency recovered after discontinuation of therapy (18). We also mentioned that besides changes in sexual arousal, the first patient reported feeling less feminine due to CGRP(-receptor) targeted drug use, highlighting the psychological and gender-related impact of sexual dysfunction (2).

In conclusion, while we agree with Dr Do that sexual dysfunction as a potential adverse event of CGRP(-receptor) targeted drugs is rare and not sex-specific, we respectfully disagree with some of his interpretations. On the contrary, we would like to encourage other clinicians and researchers to remain vigilant and to report similar cases. Doing so will, hopefully, help reduce the stigma and taboo surrounding both sexual dysfunction and migraine, improve communication and trust between patients and clinicians, offer deeper insights into the pathophysiology of migraine and the mechanisms of these new therapies, and ultimately, improve the quality of life of migraine patients – irrespective of any sex and gender identity.