The present study yielded results on the comparison between OnaBoNT-A vs. STPP plus pharmacological therapy. We opted for a pragmatic-inspired observational design rather than a Randomized Clinical Trial (RCT) because it is not possible to provide a correct randomization in trials involving a psychotherapeutic approach, since acceptance of the psychotherapy treatment is the nominal requirement for it to succeed. Although RCTs remain the gold standard to test effectiveness of treatments, the real-world efficacy can differ from results obtained by RCTs. In this context real-world and pragmatic studies can provide information on the activity of established therapies also in the setting of routine clinical practice. According to a recent article by Ford, our observational study has some characteristics that are recommended for pragmatic trials [31]: patients were recruited amongst those who usually attended our Headache Center, therapeutic interventions were chosen by different doctors based on the therapeutic guidelines and patients profile. The recruited population was therefore the closest to real world CM population candidate to receive that treatment. Both OnaBoNT-A and STPP were delivered as usual, and regular 3-month follow-up visits were used to assess the clinical response, which is the routine follow-up schedule used in our outpatients clinic.
Our study showed the overall beneficial effect on headache days and painkillers intake in OnaBoNT-A and the STPP-plus drug-of-choice groups with no difference at the last follow-up, after 12 months. Patients of the STPP plus drug group had less headache days at 3 months and less acute headache medications consumption at 3 and 6 months in both the original and PSM analyses. This suggests that on the long run the two treatments work equally well, but that STPP can have an added value in the short period. In line with this, the number of MOH patients decreased in a significant manner after 3 months only in the STPP group, according to previous data showing that STPP-associated treatment is more effective than pharmacological therapy alone at 6 and 12 months follow-up [11].
However, our study showed that STPP arm is concerned by a higher rate of dropouts, 78% (STPP) vs. 55% (OnaBoNT-A). Such rate of discontinuation is quite high but in line with recent data from the pharmacological arm of the FORWARD trial [32]. Interestingly, in the present study, the adherence dropped mostly at the time of the latest follow-up (12 months). A possible reason of the adherence in the OnaBoNT-A group could be related to the fact that, despite the global effect was similar in the two groups, OnaBoNT-A patients had a longer migraine and chronicization duration and therefore an improvement could have a more encouraging effect to sticking with the therapy as well as to the “invasive” nature of the OnaBoNT-A treatment. This pattern of dropping out could most likely reflect a failure of treatment efficacy with CM and MOH relapse and possibly in part the normal time-related turnover of attending CM patients.
From literature, we know that only 9% of patients drop and discontinue treatments for clinical improvement. We can speculate that a part of dropouts occurred for improvement, although it is likely that the larger part is due to therapy inefficacy. In our setting, in fact, both groups had the larger improvement early after the beginning of the two therapies. For STPP, it occurred just after STPP ending, when the number of headache days dropped by a third. Moreover, 8 patients became CR and didn’t start pharmacological therapy throughout the entire follow-up. As well, OnaBoNT-A patients experienced the same response after the first administration. Both groups halved the painkillers consumption at this point. In part it could also depend from the advice to quit overuse [33, 34] or as a direct consequence of the clinical improvement, but the fact that medical discontinuation was significantly higher in STPP suggests that psychotherapic intervention had an active role.
Since at baseline the two group differed for several demographic and clinical features (see Table 1 for details), we performed a PSM to mimic randomization in the two groups, as suggested in recent real-world studies [35, 36]. In our sample, patients with a longer history and more lines of failed therapies were addressed to OnaBoNT-A and patients showing depressive symptoms (who later obtained higher scores in the HAM-D) to STPP. This is not surprising since enrolled patients should be those that most likely would receive that treatment in real life. However, after matching patients with the propensity score, results were highly confirmed, strengthening their robustness. We should acknowledge that, despite PSM, age remained different between groups. Instead of forcing the PSM to reach a better match, further reducing the number of patients, we preferred to repeat the analysis with this matching. This decision derived from two main reasons. First, PSM successfully resolved 4 out of 5 bias without changing results, so it is unlikely that pairing the age would modify the outcome. Second, we decided to have more than 30 subjects per group so that the number is high enough to compensate unpredictable variables that could alter the outcome, according to the central limit theory [37].
We also investigated the role of baseline characteristics in determining early and late response, obtaining significant results for the pooled data and OnaBoNT-A group. The number of headache days per month at baseline resulted the most important predictive factors for early response, and resulted proportional to the chance of response: NR had the higher baseline number of headache days, while PR patients had an intermediate value, and CR patients had the lowest one. It suggested that achieving a better outcome is easier in patients with less days of headache, suggesting that adequate treatment should be started before frequency of headaches becomes daily (more than 25 days/month).
Baseline painkillers consumption and the level of school education are the most important factors for the 12 months response. It is interesting to notice that 3- and 12-month predictors are different. Baseline analgesic consumption is probably related to an “addiction” profile that could reappear with time and easily facilitates medication overuse and migraine chronicization [38]. On the other hand, a higher level of school education is in general associated to a better outcome in psychotherapy studies [39].