Onabotulinumtoxin‐A in Chronic Migraine: Should Timing and Definition of Non‐Responder Status Be Revised? Suggestions From a Real‐Life Italian Multicenter Experience

Abstract

Objective To clarify whether the clinical response after the first 2 cycles with Onabotulinumtoxin A can accurately predict the long‐term response. Background Onabotulinumtoxin‐A (OBT‐A) is an approved preventive treatment option for chronic migraine (CM). Nowadays, it remains to be clarified if the treatment has to be prolonged for at least an entire year (4 injections every 3 months – ie, quarterly, as proposed in the PREEMPT trials) or it can be halted after the second or third injection if not clinically effective. Design and Methods We conducted a multicenter observational cohort study based on real‐life data on the usage of OBT‐A in CM patients from 2 Italian headache centers, Roma Campus Bio‐Medico and Milano Besta, adopting the whole 4‐injections protocol. We performed a retrospective analysis of medical records of consecutive patients treated in the 2 centers. The main statistical analysis aimed to evaluate longitudinal measures related to headache (monthly headache frequency, monthly number of analgesic drugs, MIDAS). We hypothesized from our clinical practice with OBT‐A that only 2 cycles of treatment were not enough to actually define the non‐responder status to botulinum toxin A and that probably a longer time of treatment is needed to get the condition of long‐term (delayed) responder. Results We considered 115 patients from the 2 centers: 53 in Roma and 62 in Milano. Regarding the main analysis, a clear improvement in each measure was obtained at the 6 months assessment and maintained up to 12 months. Comparing patients with <30% and ≥30% reduction in headache frequency between T0 and T2 or T4 (respectively, “Non‐Responders” and “Responders”), we found that the agreement between the classification Responders/Non‐Responders at T2 and T4 was not very high (79/104 = 76.0%, with a “moderate” Cohen's Kappa of 0.51), suggesting that the status at T4 is not fully predictable by the status at T2 (λ = 0.47). Responders for headache frequency at T4 were 54.8%. Among Responders at T2, Responders at T4 were 47/62 = 75.8% (95% CI: 64.5%, 85.5%), while among Non‐Responders at T2, Responders at T4 were 10/42 = 23.8% (95% CI: 11.9%, 38.1%). Similarly, even when considering the 50% reduction in painkillers consumption or in MIDAS total score between T0 and T2 as possible prognostic factors, the changes occurring at T4 are not strongly predictable by those at T2. Conclusions A ≥30% reduction in headache frequency at T2 cut‐off is not adequate in predicting a late response to treatment: more than a quarter of excluded patients would miss a clinical improvement with an ongoing treatment, while in a similar percentage of Responders the treatment would lose efficacy. Results from our real‐life study suggest that we possibly have to postpone the definition of Responder/Non‐Responder to OBT‐A at least after 1 year of treatment (4 cycles).

The Healthy Eating Plate Advice for Migraine Prevention: An Interventional Study

“…The reduction in MMDs is to be intended as a further reduction after the effect of the ongoing preventive treatment, unchanged throughout the study. This is in line with other migraine clinical settings where the expected benefit is mild [17].…”

Benefits Beyond Headache Days With OnabotulinumtoxinA Treatment: A Pooled PREEMPT Analysis

“…Consistent with the EHF guidelines, a quarter of Italian headache physicians surveyed believed that patients achieving a ≥ 30% reduction in headache days were considered responders (instead of ≥ 50% reduction), and 40% of these clinicians believed that more than four treatment cycles were required before classifying a patient as a nonresponder [ 27 ]. In agreement with this survey, a real-world observational cohort study using the PREEMPT protocol suggests that approximately 25% of patients might not respond until after four treatment cycles and 1 year, cautioning against adjudicating responder/nonresponder status to avoid missing a significant percentage of patients who might benefit from onabotulinumtoxinA treatment [ 12 ]. Real-world data from headache centers in Italy also support the notion that the benefits of onabotulinumtoxinA treatment using the PREEMPT protocol are sustained, even in patients with a recent onset of CM [ 28 ].…”

“…For example, a patient may improve from a disabling 20 severe headache days per month to 11 moderate headache days per month. Despite this considerable clinical benefit, such a patient would not be considered a responder because headache days were not reduced by 50%, and might lose access to beneficial treatment [12].…”

OnabotulinumtoxinA Is an Effective Treatment for Chronic Migraine in Patients With Comorbid Fibromyalgia

“…This high response rate was in spite of the presence of several negative predictive factors such as long duration of CM, multiple prior preventive treatment failures, and several comorbidities. Importantly, 74.2% of patients were treated for at least 1 year, minimizing the potential confounding influence of natural fluctuations in the disease course itself (42). The 1 year span of treatment highlights the long-term safety and tolerability of OnabotA, even in the presence of comorbidities.…”

“…As per usual clinical practice, patients maintained a paper or electronic diary during the OnabotA treatment period to register headache days and acute medication intake. The first year of treatment (four cycles) was considered to analyze the effectiveness and tolerability of OnabotA (42). The primary endpoint was reduction in moderate to severe headache frequency at 3, 6, 9, and 12 months in accord with the Guidelines of the International Headache Society for controlled trials of preventive treatment of CM in adults.…”