In the present study, we report the effectiveness of monthly galcanezumab 120 mg s.c. administration in a cohort of high frequency and chronic migraine patients, with at least 3 previous preventive treatments failure, during a six-month period. Beyond the improvement of headache frequency, intensity and duration, we observed a significant improvement in scores assessing migraine related disability and impact, depressive and anxious symptoms, pain coping, cutaneous allodynia and quality of life. Furthermore, we considered a composite score derived from the product of headache frequency, headache intensity, and headache duration (the last as a proxy of response to painkillers) that, for sake of shortness, we named “whole pain burden”.
Migraine is recognized as the second-highest cause of years lived with disability, the first in patients aged between 15 and 49 years  and undertreatment strongly affect migraine related disability, especially in patients with high frequency or chronic migraine [24,25,26]. Therapeutic approach to these patients involves the use of preventive strategies based, until few years ago, only on “repositioning drugs” characterized by unsatisfactory responses but, above all, by non-excellent tolerability profiles strongly affecting patients’ adherence to treatment [3, 27, 28].
The availability of CGRP-mAbs as novel specific, effective and well-tolerated therapeutic option has represented a breakthrough in migraine preventive treatment [29, 30]. Among CGRP-mAbs, galcanezumab efficacy and safety in migraine prevention has been provided by evidences from rigorously controlled, randomized, double-blind, placebo-controlled, phase 2 or 3b studies in patients with episodic and chronic migraine as well as in both patients with previous migraine preventive medications failure (the latter data confirmed also in an Italian real-life experience) [5,6,7,8,9].
Nevertheless, previous galcanezumab studies did not deeply investigate the impact of this drug on overlooked aspects that strongly contribute to migraine burden, such as coexistent depressive and anxiety symptoms, the cognitive strategies to face with pain, experience of cutaneous allodynia as well as sleep quality.
Herein, we demonstrated the effectiveness of galcanezumab over a six-month period in a group of 43 migraine patients with documented failure to at least three migraine preventive medication classes. Specifically, we observed a decreased number of headache days per month from 20.56 to 7.44 and 6.37 with a reduction of at least 50% of headache days per month in 72.09% and 74.42% of patients after the third and the sixth administrations of monthly galcanezumab, respectively. These data are in line with those emerging from a recent prospective study showing that anti-CGRP mAbs induce a significant reduction in monthly migraine days from the first month of treatment, followed by a further slight decrease until month 6. This may suggest that at least 6 months of galcanezumab treatment are needed to reach the therapeutic plateau necessary to counteract the neurobiological mechanisms underpinning CGRP desensitization .
Beyond mere pain related parameters, several patient-reported outcomes (PROs) have been considered. In this context, the high headache impact (by means of HIT-6) and the severe disability (by means of MIDAS) as well as the critical impairment in migraine-specific quality of life (by means of MSQ) registered at the baseline showed a significant improvement after the third and, even more, the sixth monthly galcanezumab administration in these patients.
Furthermore, at baseline 46.51% and 27.91% of patients showed mild depression (by mean of HDRS and the self-administrated BDI-II) and moderate anxiety comorbidities (by mean of HARS) respectively. Statistically significant improvements have been observed since the third administration of monthly galcanenumab leading to mean scores values consistent with the absence of both depressive and anxiety contents. It is noteworthy that depressive and anxious symptoms are able to worsen migraine attacks increasing the rates of progression to chronic migraine and making migraine treatment more challenging, reducing quality of life and increasing the overall disease burden [32,33,34]. Since the greater is the burden of migraine the higher is the probability of experiencing depressive or anxious symptoms , we argue that galcanezumab related improvement of migraine frequency, severity and responsiveness to pain-killer as well as headache impact, disability and quality of life may reflect on the comorbid psychiatric symptoms.
Beyond depressive and anxiety symptoms, the 58.14% of our patients showed PCS scores at baseline above the cut-off value, witnessing negative orientation toward actual or anticipated pain experience. A significant reduction in PCS scores, in all sub-domains, was found since the third monthly galcanezumab administration.
Maladaptive pain coping strategies, consisting on negative cognitive and affective behavior in response to pain, such as the so-called “pain catastrophizing”, are well-reported in migraine patients . In particular, rumination of pain related thoughts, magnification of pain experience, and helplessness about it are strong predictors of headache outcomes and significantly associated with disability. Moreover, “pain catastrophizing” is associated with migraine chronicization, poorer treatment response, increased medical consultation, impaired functioning and psychological distress leading to reduced health-related quality of life [37,38,39].
Furthermore, in our patients group, we assessed sleep quality using the MOS-sleep scale, a self-administered scale able to evaluate 6 different disturbances (i.e. difficulty falling asleep and maintaining sleep, daytime sleepiness, respiratory disorders, presence of ronchopathy, amount of sleep). The incidence and prevalence of sleep disorders are significantly higher in migraine patients when compared to general population and sleep-wake rhythm and the quality of sleep abnormalities surely represent trigger factors for migraine attacks [40, 41]. In particular, insomnia, the most common sleep complaint among migraine patients, has been observed in 40% of episodic migraine patients and in almost 70% of chronic migraine patients, half of which also reporting snoring during sleep . Based on the present observations, no changes were found in sleep patterns considering the comprehensive “sleep problem index” in the course of galcanezumab treatment. We can speculate on the possibility that galcanezumab, similarly to other anti-CGRP monoclonal antibodies , may be able to improve sleep-wake rhythm abnormalities although longer periods are needed.
In our patient sample, 31% reported ictal cutaneous allodynia (CA) at baseline. After the third and sixth monthly galcanezumab administrations we noted a remarkable reduction of ASC-12 scores (p = 0.01) although it became not statistically significant after correction for multiple comparison. Nevertheless, we can argue that galcanezumab-induced peripheral CGRP inhibition may be able to indirectly inhibit the central trigemino-thalamic pathway sensitization known to be involved in ictal CA and, in turns, putatively inhibiting chronification mechanisms. It is well-known that CA is reported in about two-thirds of migraine patients as the perception of pain induced by trivial stimuli to normal skin, during or between headache episodes . CA is known to represent a negative predictor of response to both acute and preventive medications and, overall, a risk factor for migraine chronification . Future studies on a larger cohort of patients or aimed to assess CA changes after longer periods of galcanezumab treatment may strongly substantiate our present observations.
Finally, in line with previous observation, a significant reduction was observed in the number of monthly days with painkillers intake as well as in total painkillers intake with a significant reduction in the number of chronic migraine patients with MOH in the course of galcanezumab administration .
One of the main findings of the present study is the identification of a composite score derived from the product of headache frequency per headache intensity per headache duration (the last as a proxy of response to painkillers) in the last three months, that for sake of shortness, we named “whole pain burden” score. Previously, a composite measure has been already employed to fully assess the potential benefit of migraine treatment strategies (the so-called “total pain burden”) obtained by multiplying duration (hours) of migraine headache and maximum pain severity (0 = none, 1 = mild, 2 = moderate, 3 = severe) for each migraine headache day and summing these over the days in a month . The “total pain burden” score was created to better reflect the individual’s migraine experience and aimed to patient-centric discussions regarding treatment expectations when clinicians are evaluating options for migraine prevention. However, calculating “total pain burden” scores in clinical practice is really complex and time consuming since it is based on day-by-day calculation of headache hours, severity and duration. In other terms, we believe that the “total pain burden” score can be a useful tool in RCT settings but seems to be inadequate to the times of the real-world setting. Furthermore, the use of a 4-point scale to assess migraine attack severity to calculate the “total pain burden” is affected by a reduced sensitivity in detecting pain intensity changes. Therefore, aware of the relevance of a unique score in clinical practice, more adherent to the personal headache experience as well as to the burden of migraine on the patients’ life, we decided to consider a “whole pain burden” composite score derived from the combination of the average values of headache frequency, intensity (using a 11 point NRS), and duration. This approach let us to observe, after the third and sixth galcanezumab administration, a significant reduction of the “whole pain burden” score in migraine patients.
Interestingly, “whole pain burden” score reduction > 50% has been found in a significant percentage of patients (73.68% and 76.93% respectively after the third and the sixth monthly galcanezumab 120 mg sc administrations) with < 50% reduction in headache days per month and, therefore, to be considered, strictly speaking, poor responders to galcanezumab treatment. The partial correlation analysis demonstrated that each element employed to calculate the “whole pain burden” score significantly contributes to its determination. The value of the “whole pain burden” composite score, as a comprehensive tool to evaluate the complexity of headache experience as well as the potential benefit of migraine preventive treatments on the quality of life, is further supported by a convergent validity witnessing the correlation between the “whole pain burden” scores and a parameter of quality of life related to migraine as the MSQ.
It could be argued that a limitation of the “whole pain burden” composite score is the low weight attributed to the number of symptomatic drugs administered. On the other hand, we would underline that the “whole pain burden” is a composite score aimed to an effective and rapid evaluation of the treatment-related changes of the experience of headache. It is noteworthy that some important aspects beyond the pain experience itself are overlooked by the “whole pain burden” composite score, such as the number of pain-killers intake and the impact of the migraine accompanying symptoms. Although aware of the limits related to the patients reported outcomes (i.e. intra-personal variation in reliability, persisting in repeated applications, decrease motivation to respond etc.) , we cannot exclude that in the future, a more complex scores, encompassing the overall migraine experience, could be proposed. However, herein we have observed a notable reduction in both the number of mean monthly days with painkillers intake and total painkillers intake after the third and sixth galcanezumab administration compared with baseline.
In the present real-life experience, there were no patients reporting serious AE or willing to discontinue treatment due to poor tolerability, although a low percentage of migraine patients experienced, beside the pain in the site of injection, constipation (16.27%), acrocyanosis (6.98%), nausea (2.32%), supporting galcanezumab as highly effective preventive treatment with a very low percentage of side-effects.
Linear regression analysis showed that both low pain intensity at baseline and high PCS scores at baseline represent negative predictors of response to galcanezumab treatment. It can be speculated that, as previously demonstrated with Onabotulinumtoxin-A , the probability of being a responder to CGRP-targeting drugs may be higher in patients with increased peripheral trigeminal sensitization and CGRP production both leading to more intense headache attacks. Moreover, “catastrophizing” habits and abnormal cognitive and emotional approaches to the pain experience, are already known to be associated with poor response to preventive migraine treatments including CGRP-mAbs [37, 49].
The present study is not free from some limitations. First of all, being a non-randomized open-label study, there was no placebo or active comparator arm . However, open-label studies not necessarily overestimate the effectiveness of treatments especially when effectiveness and safety profiles are well-established, as it is with galcanezumab, in both episodic and chronic migraine. However, registering a persistency of 100% of patients in the absence of changes in preventive medications, we are exempt from unintentional bias related to long-term follow-up.