Table 1.

Characteristics of the eight studies meeting inclusion criteria for the analysis.

Study Report (Author and Year)	Study Design	Ethical Approval	Sample Size	Inclusion Criteria for Participants (Type of Migraine and of Treatments)	Intervention (n)	Control (n)	Intervention Type, Timing and Dose	Treatment Assignment, Allocation and Concealment Mechanisms	Outcome	Results	Length of Follow-Up	Limitations of the Study	Authors’ Conclusions
Armanious et al., 2021 [46]	Retrospective cross-sectional	Approved by the university’s Institutional Review Board, Pro00036880	All patients between the ages of 18 and 70 years of age seen in the university’s Headache Clinic (n = 78) with clinic encounters between 05/17/18 and 10/17/ 18. No sample power calculation	Patients between the ages of 18 and 70 years, with diagnosis of chronic migraine, defined as 15 or more headache days per month for three months with features of migraine headache on at least 8 days per month, and a baseline treatment with onabotulinumtoxinA for at least a nine-month duration. A total of 61.5% were actively using three or more other prophylactic migraine medications	n = 78	No placebo group for comparison. Comparator is represented by the patient’s baseline on onabotulinumtoxinA for a minimum of nine preceding months	Erenumab 70 mg (n = 37) and Erenumab 140 mg (n = 41) in addition to onabotulinumtoxinA injections. Time points = 30, 60 and 90 days	______	Primary outcome measure was monthly headache days (MHDs) and monthly migraine days (MMDs) at baseline, 30-, 60- and 90-days. MHDs and MMDs	Mean of 8.1 fewer MHDs (p < 0.001) and of 7.4 fewer MMDs (p < 0.001) at 90 days. Statistically significant 30% reduction at 90-days for migraine (p = 0.008), but not for headache; no statistically significant 50% reduction at 90-days for migraine or headache	Ninety days	Observational nature; lack of comparison group; lack of control of concurrent use of additional prophylactic migraine therapies; lack of control for co-morbid conditions; missing assessment of additional variables. Data were not analyzed for parameters with ≥50% missing data points	Erenumab in combination with onabotulinumtoxinA may enhance the effect on CGRP release from peripheral unmyelinated C fibers, blocking CGRP receptors in myelinated A-delta fibers. Clinically meaningful improvement in this intractable chronic migraineurs
Blumenfeld et al., 2021 [47]	Retrospective, longitudinal chart review	The study was conducted in accordance with International Council for Harmonisation guidelines and local legal requirements, and complied with the ethical principles of the World Medical Assembly. The New England Independent Review Board approved the study protocol and case report form (CRF) before study initiation	Patients aged ≥18 years referred at the Neurology Center of Southern California for chronic migraine (San Diego County, CA) between 1 October 2018, and 1 November 2019. No sample power calculation. A convenience sample of approximately 300 patients based on available charts and adequate sample size to characterize the safety profile was used	Adult patients (aged ≥ 18 years) with chronic migraine presenting at least two consecutive onabotulinumtoxinA treatment cycles without concomitant CGRP mAb therapy during the 8-month qualification period prior to the index date (the initiation of combination onabotulinumtoxinA and CGRP mAb therapy), and ≥1 month of subsequent combination treatment with onabotulinumtoxinA and CGRP mAb	n = 257	No placebo group for comparison. Comparator is represented by the patient’s baseline	Combination treatment of onabotulinumtoxinA with anti-CGRP mAbs (erenumab 70 (n = 136)/140 (n = 62) mg and galcanezumab 240 (n = 42) mg once monthly and fremanezumab 225 (n = 8)/675 (n = 7) mg once every three months as per label, instead of onabotulinum toxin not always administered per label, in dose ranging 115–200 U instead of 165U of baseline)	De-identified extracts of charts were prepared by site staff for the study	Monthly headache frequency, with intensity measured on a 0–10 scale. Migraine-related disability was captured on the Migraine Disability Assessment (MIDAS) questionnaire. Adverse events, discontinuations and reasons for discontinuation were recorded for each visit	Statistically significant and clinically meaningful reductions in mean MHDs at all visits. one-third (31.5–36.7%) of patients had a ≥50% reduction in MHDs after approximately 6 to 12 months: 43.7–45.1% of patients had a ≥5-point reduction from baseline, and 27.1–29.6% had a ≥30% reduction in MIDAS score. The mean MIDAS scores significantly decreased from baseline by 6.1 to 11.1 points during approximately 6 to 12 months of combination treatment. The 27.8% (68/245) of patients reported adverse events, with the most common being constipation (8.6% (21/245)), occurring most frequently in patients treated with erenumab (18/21). Concomitant use of other medications was recorded in 92.2% of patients at baseline, most commonly sumatriptan (20.7%) and topiramate (6.8%)	Twelve months	The onabotulinumtoxinA treatment was not always administered per label. The dates of migraine diagnosis, initiation of onabotulinumtoxinA, and headache frequency prior to onabotulinumtoxinA treatment prior to the 8-month qualification period were collected aas available. Missing data due to loss to follow-up were not included	The real-world data demonstrated that combination use of onabotulinumtoxinA and a CGRP mAb was generally well tolerated and suggestive of additive or synergistic benefit in headache frequency and migraine-related disability
Boudreau 2020 [41]	Prospective, observational study (NCT04152434)	All patients consented to participate to the study	No sample power calculation	Chronic migraineurs with migraine 15–30 days per month at baseline with or without an actual preventive drug, who failed more than 3 preventive drugs previously, naïve to monoclonal anti-CGRP mAbs	n = 69 nonpresenting reduction in migraine frequency at baseline out of n = 158 nonresponders	Group I On no preventive therapy at the start of Erenumab, (no Botox cohort) Group II On Botulinum Toxin type A prior to the add on therapy with Erenumab (Botox cohort). Group III On an oral preventive therapy prior to the add on therapy with Erenumab (no Botox cohort)	Botulinum Toxin type A + erenumab (70/140 mg)	______	The primary objective, was the reduction in the frequency of monthly migraine days. Adverse events were a secondary outcome	Forty-five patients (65%) experienced a decrease in the frequency of their monthly migraine days by 5–7 days, becoming episodic. Seventy-two adverse events were experienced during the 9 months of treatment, 56 events with the 140 mg. dose (118 patients), and 16 events with the 70 mg. dose (40 patients), the most frequent being comnstipation (34% of patients)	Nine months	Fifteen patients were lost to follow up. Fifty seven percent of patients failed to reach the primary end point	The 65% of patients receiving combination therapy achieved reduction in migraine frequency, instead of the 26% with erenumab alone or the 15% with erenumab in combination with prophylactic treatments other than botulinum toxin A
Mechtler et al., 2022 [48]	Retrospective, noninterventional, longitudinal study	The New England Independent Review Board (IRB) reviewed the study protocol prior to study initiation and determined the study as exempt from review. This study was conducted in accordance with current applicable regulations, International Conference of Harmonization guidelines, and local legal requirements, and complies with the ethical principles of the World Medical Assembly	All the eligible patients treated at the DENT Headache Center (Buffalo, NY, USA) between 1 June 2018 and 15 March 2020. The index date was defined as the start of combination treatment with onabotulinumtoxinA and a CGRP mAb and occurred between 1 June 2018 and 15 March 2019. The target sample size was up to ~300 patients, the expected number of eligible patients at the site	Adult patients (≥18 years) with chronic migraine treated with ≥2 consecutive cycles of onabotulinumtoxinA before ≥1 month of continuous onabotulinumtoxinA and CGRP mAb (erenumab, fremanezumab, or galcanezumab) combination treatment	n = 148	No placebo group for comparison. Comparator is represented by the patient’s baseline. A baseline period of 1–3 months prior to index was used to assess the effectiveness of onabotulinumtoxinA treatment monotherapy. At baseline most used concomitant migraine medications (n = 143/148, 96.6%) and presented comorbid conditions (n = 142/148, 95.9%)	Continuous onabotulinumtoxinA and CGRP mAb [erenumab (70–140 mg), fremanezumab (225 mg), or galcanezumab (120 mg)] combination treatment	De-identified data were used	Headache frequency (monthly headache days). The effect on quality of life and disability was assessed with the 6-Item Headache Impact Test (HIT-6) and Migraine Disability Assessment (MIDAS), respectively. Adverse and serious adverse events were reported	After 12 months of combination therapy, MHD decreased by a mean of 4.6 days (95% CI 2.5–6.7). The 34.9% (95% CI 21.0–50.9) patientsachieved ≥50% reduction in MHD. Adverse events were reported by 18 patients (12.2%), with the most common being constipation (n = 8, 5.4% [onabotulinumtoxinA plus erenumab only]) and injection site reactions (n = 5, 3.4%)	Twelve months	Per label, erenumab, fremanezumab, and galcanezumab were administered once monthly, while OnabotulinumtoxinA was not always administered per label. Results were based on available data and missing data were not included. In fact, since paired HIT-6 and MIDAS scores from baseline and post-index assessments were only available for up to four patients, no further analyses were reported for those outcome measures	Incremental and clinically meaningful reductions in MHD are provided by combination therapy
Nandyala et al., 2022 [49]	Retrospective, cohort study	The study was approved by Institutional Review Board, and patient consent was deemed not needed. However, before the beginning of the therapy with erenumab, patients were provided information on expected side effects	Patients at Medstar Georgetown Headache Center. No sample size calculation	Adult (≥18 years old) patients who had a diagnosis of chronic migraine receiving onabotulinumtoxinA	n = 50 (2 patients started with 70 mg erenumab and moved to the 140 mg group)	No placebo group for comparison. Comparator is represented by the treatment with onabotulinumtoxinAlone	Erenumab [70 (n = 22)/140 (n = 26) mg) in combination with onabotulinumtoxinA, n = 50	All data were de-identified, collected and recorded in a password protected document	Primary endpoint was decrease in number of migraine days. Secondary endpoints included a decrease in headache days and reported side effects	Significant reduction in MMDs (11.3 ± 9.3 vs. 14.9 ± 9.4, p < 0.001) and of MHDs (18.2 ± 10.3 vs. 20.7 ± 9.1, p = 0.042); 6 patients reported mild side effects including dizziness, insomnia, fatigue, skin changes, constipation and hair loss	One month	Data about demographic characteristics, other prophylactic medications, co-morbidities and number of prior treatments were not gathered	Erenumab and onabotulinumtoxinA, when used in combination, Show a decrease in migraine days per month and in headache days per month, without severe side effects
Ozudogru et al., 2020 [40]	Retrospective, observational, chart	_____	Patients diagnosed with chronic migraine, having received at least two onabotulinumtoxinA treatments, after June 2018, and currently prescribed erenumab, fremanezumab or galcanezumab. No sample power calculation	Patients with a diagnosis of chronic migraine, who received at least two onabotulinumtoxinA treatments, after June 2018, and currently prescribed erenumab, fremanezumab or galcanezumab	n = 36	No placebo group for comparison. Comparator is represented by the treatment with onabotulinumtoxinAlone	OnabotulinumtoxinA in combination with erenumab, fremanezumab or galcanezumab	______	1. number of headache days; 2. number of weeks until the benefit from wear-off; 3. number of headache days after the benefit wore off	Half of the patients (n = 18) demonstrated improvement in headache burden >50% after the addition of an anti-CGRP mAb and an average increase of 2.0 weeks taken to wear-off during combination treatment	______	Small sample size. Retrospective, single-site study. Answers to the pre-procedure questionnaire used were based on the patients’ own recollection of events, with potential for recall bias	Potential for anti-CGRP mAbs to prolong the therapeutic benefit of onabotulinumtoxinA and to delay the wear-off by average two weeks
Silvestro et al., 2021 [50]	Case series	Approved by Ethical Committee of the University of Campania Luigi Vanvitelli. Each patient gave informed consent	No sample power calculation	Patients, aged between 18 and 65 years, who failed at least four or more oral preventive medication classes (propranolol or metoprolol, topiramate, flunarizine, valproate, amitriptyline, or candesartan) due to lack of efficacy or intolerable side effects, prescribed with onabotulinumtoxinA for at least 9 months (e.g., three administrations of 185 UI), interrupted in favor of a 6-month erenumab 140 mg monthly administration	n = 10	No placebo group for comparison. Comparator is represented by baseline	Combined treatment with onabotulinumtoxinA (185 UI quarterly administration) and erenumab (140 mg monthly administration)	______	MHDs, severity of headache during attacks, symptomatic drug intake per month, and migraine disability	Statistically significant reduction of MHDs (p < 0.01), intensity of headache during attacks (p < 0.01), and symptomatic drug intake per month (p < 0.01), as well as MIDAS-assessed migraine disability (p < 0.01), compared to the baseline and also to onabotulinumtoxinA or erenumab alone (p < 0.01). The 30% of patients reported pain in the injection sites, without serious adverse events	Six months	Small sample size	A combined therapy may provide an additive or synergistic effect on the trigeminal nociceptive pathway
Toni et al., 2021 [51]	Case series	No approval since the study is based on authors’ clinical experience	Patients admitted between May 2018 to June 2020. No sample power calculation	Chronic migraine with suboptimal response to onabotulinumtoxinA	n = 17	No placebo group for comparison. Comparator is represented by response to onabotulinumtoxinA alone	Combined therapy with onabotulinumtoxinA and fremanezumab (n = 9), erenumab (n = 4) or galcanezumab (n = 4)	Patients’ records confidentiality was maintained and data de-identified	Headache days and severity over 1–6 months	A mean improvement of +12.6 headache-free days was observed in fremanezumab patients, +6.4 in erenumab patients, and +3.8 in galcanezumab patients, for a total improvement experienced by n = 11 patients. No severe adverse side effects were experienced, with only mild irritation at the injection site and constipation. The response rate resulted of 58.82% for headache days reduction and of 64.71% for headache severity	Six months	Placebo-controlled, randomized studies are required to confirm the results	Patients suffering from severe, intractable migraine may benefit from onabotulinumtoxinA and anti- CGRP mAb dual therapy, likely due to a synergistic mechanism at receptor and ligand level