Abstract
Background:
Zavegepant nasal spray is a novel CGRP receptor antagonist that has been developed for the acute treatment of migraine – a prevalent disease leading to disability and economic burden. The meta-analysis aims to quantify the efficacy of Zavegepant compared to standard care or placebo in achieving pain freedom, freedom from most bothersome symptoms (MBS), sustained pain freedom, and pain relapse at 2 to 48 hours.
Methods:
Databases and registers were systematically searched to identify relevant clinical trials. Two independent reviewers used a standardized data extraction form to collect relevant data on primary and secondary outcomes. Statistical analysis was performed in RevMan 5.4 software. The efficacy of Zavegepant was compared to placebo using odds ratios (OR) with 95% confidence intervals (CI). Heterogeneity was assessed using the I2 statistic, chi-square test, Z value, and P value. Cochrane ROB-2 and ROBINS-I tools were used to assess the biases (osf.io/b32ne).
Results:
Of 36 identified studies, 3 were included in this meta-analysis. Zavegepant was more effective in achieving pain freedom (OR: 1.6, P < .00001), and freedom from MBS at 2 hours (OR = 1.4, P < .00001). The intervention group demonstrated a higher likelihood of sustained pain freedom between 2 and 48 hours (OR = 1.74, P < .00001). Although there was a trend towards reduced pain relapse between 2 and 48 hours in the intervention group, the difference was insignificant (OR = 0.67, P = .11).
Conclusion:
This meta-analysis confirms the effectiveness of Zavegepant nasal spray in treating acute migraine, with significant improvements in pain and symptom relief. Further research is needed to determine the effect on pain relapse and overall safety.
Keywords: CGRP antagonists, meta-analysis, migraine, nasal spray, Zavegepant
1. Introduction
Migraine is a the third most common disease worldwide characterized by current episodes of severe headaches, typically accompanied by nausea and vomiting with sensitivity to sound and light.[1] Although the exact pathophysiology of migraine remains incompletely understood, it is believed to involve complex interactions between genetic, environmental, and neurovascular factors.[2] The Global Burden of Disease estimates that the 1-year prevalence of migraine is 14.7% worldwide.[3–5] Nearly 1 in 5 people are affected by migraine at some point in the lifetime.[5] At present, there are no underlying trends of geographical relationships related to prevalence. Migraine significantly impacts global health, afflicting more than 10% of individuals around the world, which is roughly 1 billion people. It ranks as the second most prevalent reason for years of life spent in disability on a global scale.[6] Women tend to experience longer durations of attacks with greater disability, and increased risk of headache recurrence.[7] The International Headache Society categorizes migraine as with (an estimated 30% of attacks) or without aura (nearly 70% of attacks).[8] Migraines can significantly impair an individual quality of life and lead to substantial economic burdens due to reduced productivity and increased healthcare utilization.[9] The heavy economic burden is due to primary case visits, pharmaceutical treatments, specialist visits, diagnostic tests and also hospitalizations. In the United States, the annual direct costs due to migraine were estimated at $9.2 billion and remained the same between 2004 and 2013.[10] Numerous patient reported outcome (PRO) measures have been developed for use in clinical trials and in the clinic.[11] The Migraine Disability Assessment Questionnaire covers housework, school work/work, and social/family/leisure activities. There are other PRO tools including the headache impact test, the Migraine-Specific QoL Questionnaire amid others.[12]
Current available treatment options for acute migraine attacks include acetaminophen, triptans, ergotamine derivatives, antiemetic medications, and nonsteroidal anti-inflammatory drugs.[13–15] The management of acute migraine episodes primarily aims to provide rapid and effective relief from pain and associated symptoms, while minimizing adverse effects and the risk of medication overuse.[16,17] Despite the availability of these treatments, a significant proportion of patients do not achieve satisfactory relief, experience intolerable side effects, or have contraindications to their use.[18] Clinical trials have been underway to test for calcitonin gene-related peptide (CGRP) receptors in the context of PROs, and quality of life benefits. Therapies are being tested to ascertain the role in chronic and episodic migraine. Zavegepant is a novel, small molecule CGRP receptor antagonist that has been developed for the acute treatment of migraine.[19] The blockade of CGRP receptors is thought to attenuate the neurogenic inflammation and vasodilation associated with migraine pathophysiology.[20]
While this meta-analysis focuses on Zavegepant nasal spray as a treatment for acute migraine, several alternative treatments have been investigated or are currently in development. These alternatives may provide additional options for patients who do not respond well to existing treatments, have contraindications, or experience intolerable side effects. Some of these alternatives include the following.[21–23] Other small molecule CGRP receptor antagonists, such as ubrogepant, rimegepant, and atogepant, have shown promise in the acute and preventive treatment of migraine; monoclonal antibodies targeting CGRP or its receptor targeted monoclonal antibodies such as galcanezumab, erenumab, fremanezumab, and eptinezumab have demonstrated efficacy in preventing migraine but have not been extensively tested for acute treatment. Non-pharmacological approaches, such as transcranial magnetic stimulation, and external trigeminal nerve stimulation, and vagus nerve stimulation have been investigated as alternative treatments for migraine, with varying degrees of success. Combining medications with different mechanisms of action, such as triptans and nonsteroidal anti-inflammatory drugs or acetaminophen, may provide synergistic effects and improved outcomes for some patients. Novel compounds targeting different pathways implicated in migraine pathophysiology, such as serotonin 5-HT1F receptor agonists (e.g., lasmiditan) and glutamate receptor antagonists, are currently under investigation and may offer additional therapeutic options in the future.
Zavegepant is administered intranasally, which may offer advantages in terms of rapid onset of action, ease of use, and bypassing first-pass metabolism.[24] Zavegepant nasal spray was approved by the U.S. Federal Drug Administration in March 2023.[25,26] Zavegepant nasal spray is currently available in 10 mg single dosage and has shown premise for acute migraine. By examining the efficacy of Zavegepant nasal spray in the acute treatment of migraine, this meta-analysis aims to contribute to the growing body of evidence supporting the development of novel therapeutic options for migraine sufferers. The evaluation of Zavegepant, alongside the exploration of alternative treatments, can help to create a more comprehensive and personalized approach to migraine management.[27] By identifying effective and well-tolerated treatment options, clinicians can better tailor treatment plans to the individual needs of their patients, ultimately improving patient outcomes and reducing the overall burden of migraine on individuals and the community.
The key objective of this meta-analysis is to quantify the following 4 outcomes among intervened patients compared to standard care approaches or placebo: at 2 hours, pain freedom, freedom from most bothersome symptoms (MBS); between 2 and 48 hours, sustained pain freedom, and pain relapse.
2. Methods
2.1. Search strategy and eligibility criteria
This meta-analysis was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Statement 2020 guidelines.[28] The following databases were searched: Cochrane Library, PubMed/MEDLINE, Scopus, and Embase. The search was conducted from inception to March 18 2023, with no language restrictions. An additional search of ClinicalTrials.Gov was also conducted. The search strategy included the terms “Zavegepant,” “migraine,” and “nasal spray,” as well as relevant synonyms and MeSH terms. In addition, the reference lists of relevant articles and conference proceedings were manually searched for additional studies (umbrella methodology).
Two independent reviewers screened the titles and abstracts of the identified articles for eligibility. Full-text articles were retrieved for articles that met the inclusion criteria. Studies were included if they were randomized controlled trials (RCTs) that evaluated the efficacy and safety of Zavegepant nasal spray for the acute treatment of migraine. Open-label trials were excluded from the meta-analysis but were discussed in the systematic review portion. Studies that did not report relevant outcomes or included insufficient data were also excluded.
3. Data extraction and synthesis
Data were extracted using a standardized data extraction form. Extracted data included author, year or ID, title, methodology, arms and interventions, inclusion criteria, primary outcomes, participants’ characteristics, efficacy, and safety. The primary outcomes of interest for the quantitative, meta-analytical portion were the proportion of patients with pain relief at 2 hours, the proportion of patients with pain freedom at 2 hours, and the proportion of patients with sustained pain freedom at 24 hours. These findings were extracted onto a data sheet. Secondary outcomes included adverse events.
4. Statistical analysis
The statistical analysis was carried out with the use of Review Manager 5.4 software, which calculated odds ratios (OR) with 95% confidence intervals (CI) for each study. OR was calculated to determine the efficacy of Zavegepant nasal spray compared to placebo for each outcome measure. An OR >1 indicated that the intervention (Zavegepant nasal spray) was more effective than placebo, while an OR <1 indicated that the intervention was less effective than placebo. ORs were considered statistically significant if their 95% CI did not include 1. The overall effect size was calculated using a random-effects model. The I2 statistic was employed to assess heterogeneity, which measures the proportion of total variation in study estimates attributed to heterogeneity rather than chance. Heterogeneity was considered significant if the I2 value was above 50%. In addition to the I2 statistic, the meta-analysis also assessed heterogeneity using the chi-square test with a significance level of 0.10. The chi-square test evaluates the null hypothesis that all studies in the meta-analysis have the same effect size. If the chi-square test is significant, it suggests that the studies are significantly heterogeneous, meaning that the differences between the study results are more than what would be expected by chance alone. To further evaluate the degree of heterogeneity, the meta-analysis also looked at the Z value and P value associated with the chi-square test. The Z value is a standardized measure of the difference between the observed heterogeneity and the expected heterogeneity under the null hypothesis. A Z value >1.96 (corresponding to a P value <0.05) indicates that there is significant heterogeneity among the studies. Overall, the meta-analysis used multiple methods to assess and quantify heterogeneity among the included studies, including the I2 statistic, chi-square test, Z value, and P value. These methods help to ensure that the meta-analysis accurately captures the variation in effect sizes across the studies and can provide a more reliable estimate of the overall treatment effect.
5. Risk of bias assessment
Randomized controlled trials (RCTs) were assessed for risk of bias using Cochrane Risk of Bias (ROB) 2 tool. Two independent reviewers assessed the risk of bias for each study. The ROB 2 tool evaluates bias across 5 domains, including bias arising from the randomization process, bias due to deviations from intended interventions, bias due to missing outcome data, bias in the measurement of the outcome, and bias in the selection of the reported result. Risk of Bias in Non-randomized Studies of Interventions (ROBINS-I) was used in our study to assess the risk of bias in the included non-randomized clinical trials. ROBINS-I is a tool designed to assess the risk of bias in non-randomized studies of interventions, including cohort and case-control studies. It evaluates the risk of bias across 7 domains, including confounding, selection of participants, classification of interventions, deviations from intended interventions, missing data, measurement of outcomes, and selection of reported results.
6. Protocol registration and funding role
The protocol of this meta-analysis is attached in the Supplementary Materials, http://links.lww.com/MD/K328. This study is registered in the Open Science Framework: https://osf.io/b32ne. No funding was obtained.
7. Results
In the identification phase, a total of 36 study records were identified from the databases and registers of which 4 duplicates were removed before screening for titles and abstracts. In the screening phase, 32 studies were reviewed for titles and abstracts, 8 were excluded as they did not meet the inclusion criteria, 24 were sought for retrieval and assessed for eligibility, and finally 21 were excluded as they were not clinical trials and/or were secondary studies. In the inclusion phase, 3 studies were included in this meta-analysis (Fig. 1).
Figure 1.
PRISMA flowchart depicting the study selection process. PRISMA = Preferred Reporting Items for Systematic Reviews and Meta-Analyses.
The kappa score for the study was 0.915, indicating a high level of agreement between raters or evaluators. This score suggests that the results are reliable and consistent across different observers in the study.
8. Overview of all the included studies
In total, 2 RCTs and 1 open-label trial was included. The total participant count was 2850. The characteristics of the included studies are presented in Table 1.
Table 1.
Characteristics of the included clinical trials.
Author, yr or ID | Title | Methodology | Arms and interventions | Inclusion criteria | Primary outcomes | Participants | Efficacy | Safety |
---|---|---|---|---|---|---|---|---|
Croop, 2022 | Zavegepant nasal spray for the acute treatment of migraine: A Phase 2/3 double-blind, randomized, placebo-controlled, dose-ranging trial | Randomized, placebo-controlled, triple (participant, care provider, investigator) masked, double blind, dose-ranging trial; Phase 2/3 (NCT03872453) | 3 experimental arms: Zavegepant (other name: BHV3500) 5 mg, 10 mg, and 20 mg (a single intranasal dose of Zavegepant 5/10/20 mg on occurrence of migraine that reached moderate or severe intensity within 45 d after randomization. The dose was administered using Aptar UDS liquid spray device); 1 placebo arm (single intranasal dose of Zavegepant-matching placebo) | At least 1-yr history of migraines (with or without aura), consistent with the International Classification of Headache Disorder, 3rd Edition: Migraine attacks present for >1 yr; age of onset <50 yr; lasting 4–72 h when untreated; <8 moderate-severe attacks per month; >2 consistent migraine headache (moderate-severe) attacks in the 3 mo prior to screening; <15 d with headache (migraine or non-migraine) per month; prophylactic migraine medication was permitted given a stable dose for at least 3 mo before screening; contraindications for triptans use was overlooked if they met all other criteria | Two-hours post-dose: percentage of participants with freedom from pain, percentage of participants with freedom from MBS | 2154 participants enrolled (22.3% discontinued); 1673 participants aged 18 to 79 yr were randomized into the safety (n = 1588) and efficacy population (5 mg, n = 387; 10 mg, n = 391; 20 mg, n = 402; placebo, n = 401) | Zavegepant 10 mg and 20 mg were more effective than placebo for the co-primary endpoints of pain freedom at 2h-postdose [(placebo: 15.5%, 10 mg: 22.5%, P = .0113) (20 mg: 23.1%, P = .0055)] and freedom from MBS [(placebo: 33.7%; 10 mg: 41.9%, P = .0155) (20 mg: 42.5%, P = .0094)]. 5 mg dose findings were insignificant | Most common TAEAs were mild or moderate including dysgeusia (13.5–16.1%), nausea (2.6–4.1%), nasal discomfort (1.3–5.2%); only SEA was thrombosis (10 mg group, 1 participant); no indication of hepatotoxicity |
Lipton, 2023 | Safety, tolerability, and efficacy of Zavegepant 10 mg nasal spray for the acute treatment of migraine in the USA: a phase 3, double-blind, randomized, placebo-controlled multicentre trial | Double-Blind, Randomized, Placebo-controlled, Safety and Efficacy Trial; Phase 3 (NCT04571060) | One experimental arm of Zavegepant (BHV3500): Participants administered a single intranasal dose of Zavegepant 10 mg on occurrence of migraine with moderate or severe intensity within 45 d after randomization. The dose was administered using an Aptar UDS liquid spray device; 1 dose of matching placebo | At least 1-yr history of migraines (with or without aura), consistent with the International Classification of Headache Disorder, 3rd Edition: Migraine attacks >1 yr; age of onset <50 yr of age; attacks, on average, lasting 4–72 hours if untreated; within the last 3 mo, <8 attacks of moderate to severe intensity; >2 consistent migraine headache attacks (moderate or severe intensity) <15 d with headache (migraine or non-migraine) per month; prophylactic migraine medication with stable dose and constant dose; contraindicated for triptans was permitted if all other inclusion criteria was followed; male/female participants ≥ 18 yr old | Two-hours post-dose: percentage of participants with freedom from pain, percentage of participants with freedom from MBS | 1978 participants were recruited, 1405 met the eligibility, of which 703 were assigned to Zavegepant and 702 to placebo; 1269 were included in the efficacy analysis set (Zavegepant, n = 623; placebo, n = 646) | Two hours after the treatment dose: pain freedom in the Zavegepant compared to the placebo group was 24% vs 15% (P < .0001); freedom from MBS was 40% vs 31% respectively (P = .0012) | Most common AEs were dysgeusia (21%), nasal discomfort (4%), and nausea (3%); no hepatotoxicity was identified due to Zavegepant |
NCT04408794, 2023 | Long-term Safety Study of BHV-3500 (Zavegepant*) for the Acute Treatment of Migraine | Open-label, Long-Term, Safety Trial; Phase 2/3 | One experimental arm of Zavegepant only: 10 mg of intranasal administration up to 8 times per month up to 1 yr | 2–8 moderate to severe migraines/month; migraine attacks present >1 yer; age of onset <50 yr; attacks, on average, lasting about 4–72 h if untreated; >15 d with headaches (migraine or non-migraine) per month; ability to distinguish migraine attacks from tension/cluster headaches; participants with contraindications for triptans could be included if they meet all other study criteria | Up to 52 wk: number of participants with AEs, SAEs, and AEs leading to discontinuation; number of participants with clinically significant laboratory abnormalities | 974 participants enrolled, while 341 completed the study | Of 603, 460 participants experienced AEs, and 7 experienced SAEs; 41 participants discontinued the study due to AEs | Clinically significant laboratory abnormalities were seen for ALT (n = 3), AST (n = 5), CK (n = 13), LDL (n = 15), and neutrophils (n = 2); 0% all-cause mortality was documented |
AEs = adverse events, ALT = alanine transaminase, AST = aspartate aminotransferase, CK = creatine kinase, LDL = low-density lipoprotein, MBS = most bothersome symptom, NCT = National Clinical Trial, SAEs = serious adverse events, TEAEs = treatment emergent adverse events, UDS = Unidose System.
Croop et al (2022) led a phase 2/3 double-blind, placebo-controlled, randomized, dose-ranging trial. The authors evaluated the safety and efficacy of Zavegepant in the form of a nasal spray in treating acute migraine.[29] The total number of participants enrolled was 2154, however 1673 were subsequently randomized into efficacy (N = 1581) and safety populations (N = 1588). Three experimental arms comprised 5 mg, 10 mg and 20 mg interventional groups along with a placebo arm. The primary outcomes were freedom from MBS and pain at 2 hours post-intervention. The findings depicted that 10 mg and 20 mg doses were significant for both primary outcomes. Pain freedom at 2 hours post-dose was achieved by 22.5% of participants in the 10 mg group (P = .0113) and 23.1% in the 20 mg group (P = .0055), compared to 15.5% in the placebo group. Freedom from MBS at 2 hours post-dose was reported by 41.9% of participants in the 10 mg group (P = .0155) and 42.5% in the 20 mg group (P = .0094), compared to 33.7% in the placebo group. The 5 mg group findings were insignificant. The most common treatment-related adverse events included nausea (2.6–4.1%), dysgeusia (13.5–16.1%) and nasal discomfort (1.3–5.2%). Only 1 patient reported thrombosis in the 10 mg group; overall, no hepatotoxic effects were reported. In sum, the study by Croop et al (2022) provided evidence supporting the efficacy and safety of Zavegepant nasal spray, specifically the 10 mg and 20 mg doses, in the acute treatment of migraine.
Lipton et al (2023) led a phase 3, randomized, double-blind, placebo-controlled trial across multiple centers in the United States. The authors aimed to investigate the tolerability, safety and efficacy of 10 mg Zavegepant nasal spray in treating acute migraine.[30] In total, 1978 individuals were recruited whereas only 1405 met the selection criteria; of these 702 were given placebo whereas 703 were given intervention. in the efficacy analytical set, 623 were Zavegepant, while 646 were given placebo. The primary outcomes were 2-hour post-dose freedom from MBS and pain. Pain freedom at 2 hours post-dose was reported by 24% of participants in the Zavegepant group compared to 15% in the placebo group (P < .0001). Freedom from MBS at 2 hours post-dose was achieved by 40% of participants in the Zavegepant group compared to 31% in the placebo group (P = .0012). For the safety of intervention, the most common adverse events were nausea (3%), nasal discomfort (4%) and dysgeusia (21%). Lipton et al (2023) provided evidence supporting the safety, tolerability, and efficacy of Zavegepant 10 mg nasal spray in the acute treatment of migraine, with significantly better outcomes in pain freedom and freedom from MBS compared to the placebo group.
In the open-label, long-term phase 2/3 trial (NCT04408794), BHV-3500 (Zavegepant) was assessed in doses of 10 mg given for up to 1 year, and a maximum of 8 times per month.[31] The total enrollment was 974, while 341 participants completed the trial. The primary outcomes included serious adverse events, any adverse events, and discontinuation due to side-effects. The number of patients that presented with laboratory abnormalities until the 52-week period was also assessed. Out of the 603 participants that were analyzed for outcomes, 460 experienced adverse events, and 7 reported serious ones. Overall, 460 experienced AEs (76.3%), and 7 experienced SAEs (1.2%). The most common AEs included dysgeusia (39.1%), nasal discomfort (10.3%) and nausea (6.1%). A total of 41 participants discontinued the study due to AEs. Laboratory abnormalities were seen for low density lipoprotein (2.5%), creatine kinase (2.2%), aspartate aminotransferase (0.8%), alanine transaminase (0.5%), and neutrophils (0.3%). No effects on mortality were reported, whereas only a small proportion discontinued the study due to adverse events. Overall, the open label trial supported outcomes of long-term safety with treatment.
9. Meta-analytical findings
This meta-analysis investigates the efficacy of Zavegepant nasal spray in the acute treatment of migraine, with 4 primary outcomes comparing intervention and placebo groups. Figure 2 displays the forest plots of outcomes.
Figure 2.
Forest plot depicting all four primary outcomes: Pain freedom, 2 h (OR: 1.6, 95% CI: 1.35–1.9); MBS freedom, 2 h (OR: 1.4, 95% CI: 1.23–1.61); Sustained Pain Freedom, 2 to 48 h (OR: 1.74, 95% CI: 1.4–2.16), and Pain Relapse, 2 to 48 h (OR: 0.67, 95% CI: 0.41–1.09).
The results demonstrate that Zavegepant nasal spray is significantly more effective in achieving pain freedom at 2 hours compared to the placebo (OR = 1.6, 95% CI = 1.35–1.9, P < .00001). The heterogeneity analysis showed no significant variation across the included studies (Tau²=0.00, Chi² = 1.42, df = 3, P = .7, I² = 0%). Concerning MBS freedom, Zavegepant nasal spray was also significantly more effective in achieving freedom from the most bothersome symptom at 2 hours compared to the placebo group (OR = 1.4, 95% CI = 1.23–1.61, P < .00001). No significant heterogeneity was found across the studies (Tau²=0.00, Chi² = 0.69, df = 3, P = .88, I² = 0%). The intervention group demonstrated a significantly higher likelihood of sustained pain freedom between 2 and 48 hours compared to the placebo group (OR = 1.74, 95% CI = 1.4–2.16, P < .00001). Heterogeneity analysis revealed no significant differences across the studies (Tau²=0.00, Chi² = 1.17, df = 3, P = .76, I² = 0%). Although there was a trend towards reduced pain relapse between 2 and 48 hours in the intervention group, the difference was not statistically significant (OR = 0.67, 95% CI = 0.41–1.09, P = .11). Heterogeneity was moderate among the included studies (Tau²=0.15, Chi² = 7.32, df = 3, P = .06, I² = 59%).
This meta-analysis provides strong evidence supporting the use of Zavegepant nasal spray in the acute treatment of migraine. The intervention group exhibited significantly better outcomes for pain freedom at 2 hours, freedom from the most bothersome symptom at 2 hours, and sustained pain freedom between 2 and 48 hours, compared to the placebo group. However, the effect on pain relapse between 2 and 48 hours was not statistically significant.
10. Risk of bias assessment
Concerning the risk of bias in the included RCTs, there were low concerns for the randomization process, deviations from the intended interventions, missing outcome data, and selection of the reported result. However, Croop and colleagues’ RCT had some concerns for bias in the measurement of the outcome. Overall, both RCTs by Croop et al and Lipton et al had low concerns. The open-label trial (NCT04408794) presented with low concerns due to confounding, selection of participants, classification of interventions, and measurement of outcomes; however, there were moderate concerns for deviations from the intended interventions, missing data, and selection of the reported result. Overall, there was a moderate risk of bias. The traffic light plot for the risk of bias is attached in Figure 3.
Figure 3.
Risk of bias assessment using ROB 2 and ROBINS-I tools (Cochrane) of all the included trials. ROB = risk of bias, ROBINS-I = Risk of Bias in Non-randomized Studies of Interventions.
11. Discussion
The present meta-analysis investigated the efficacy of Zavegepant nasal spray for the acute treatment of migraine, focusing on 4 primary outcomes in comparison with a placebo group. Our findings provide strong evidence for the effectiveness of Zavegepant nasal spray in managing acute migraine episodes. A total of 2850 participants were meta-analyzed, of which 623 were in the interventional group and 646 were in the placebo group. The results demonstrated that patients treated with Zavegepant were significantly more likely to achieve pain freedom at 2 hours, freedom from the MBS at 2 hours, and sustained pain freedom between 2 and 48 hours. These findings highlight the potential benefits of Zavegepant as an acute migraine treatment option, particularly in terms of rapid and sustained relief from pain and other bothersome symptoms. It is important to note that the heterogeneity in the results for these 3 outcomes was low, indicating consistent effects across the included studies.
However, the meta-analysis did not find a statistically significant effect of Zavegepant on pain relapse between 2 and 48 hours, with moderate heterogeneity observed among the studies. The non-significant effect on pain relapse could be attributed to various factors, such as differences in the studied populations, migraine severity, or study designs. Additionally, the moderate heterogeneity suggests that further research is warranted to explore the potential sources of variability in pain relapse outcomes.
Essentially Zavegepant when administered in a nasal formulation works as a small molecule CGRP receptor antagonist, leading to reduced migraine pain, light and sound sensitivity and nausea.[32] CGRP is a protein in the brain and nervous system, which is involved in pain transmission; it is pertinent chemical messenger, which is the target of severe experimental and clinical studies to manage pain and other migraine symptoms.[32,33] As a chemical messenger, CGRP is made up of small chains of amino acids that is both released and synthesized in the nerve fibers or neurons.[34,35] The cost of Zavegepant nasal spray is not currently available, however, GlobalData Healthcare reports that as a class of the gepant drug, it will be the first and only intranasally given intervention or migraine.[36,37] Current treatment recommendations state that the nasal administration must be given in 1 nostril only, at 10 mg or 20 mg doses. A review reported in 2013 that nasal sprays may help ease symptoms of acute migraine attacks, that are quality-of-life hampering within 15 minutes.[38] Overall, nasal sprays are viable modalities of treatment because they deliver rapid symptom relief by curbing pain and inflammation, and improve PRO.[39]
Our meta-analytical study collates current evidence of Zavegepant nasal spray.[40] When considering treatment options for acute migraine attacks, rapidity and sustained pain relief are 2 key indicators. We reported pain relief and MBS relief within 2 hours of use. However, pain relapse findings at the 48-hour timepoint were inconclusive, warranting further research to better understand this outcome. Ongoing and future clinical studies must assess the real-world PRO of nasal sprays for acute migraine. Furthermore, researchers must be mindful of additional adverse events other than vomiting, nausea or nasal discomfort. Allergic reactions such as hives and face swelling may be subjected to patient-level use.
12. Strengths and limitations
The strengths of this meta-analysis include the comprehensive search strategy, rigorous selection criteria, and the utilization of established statistical methods to synthesize and analyze the data. However, some limitations should be considered when interpreting the results. First, the number of included studies was relatively small, which may limit the generalizability of the findings. Second, the meta-analysis focused solely on the efficacy outcomes, and a comprehensive evaluation of safety and tolerability was not included. Future research should assess the safety profile of Zavegepant to ensure a comprehensive understanding of its risk-benefit profile in the acute treatment of migraine.
13. Recommendations
Key recommendations for future trials and secondary studies are as follows:
Conduct larger, multicenter, randomized controlled trials to validate and expand upon the findings of this meta-analysis, as well as to enhance the generalizability of the results to a broader population of migraine sufferers.
Investigate the effect of Zavegepant nasal spray on pain relapse in more detail by exploring potential sources of variability, such as differences in study populations, migraine severity, concomitant medications, and study designs. This may help to elucidate the reasons for the inconclusive findings in the current meta-analysis.
Assess the safety and tolerability of Zavegepant nasal spray in both short-term and long-term use, as these factors are crucial in determining the risk-benefit profile of the treatment for patients experiencing acute migraine episodes.
Perform subgroup analyses and meta-regression to identify potential factors that may influence the efficacy of Zavegepant, such as age, sex, migraine subtype, and migraine frequency. This information could help to guide personalized treatment strategies and optimize outcomes for individual patients.
Conduct cost-effectiveness analyses to evaluate the economic impact of incorporating Zavegepant nasal spray into the standard of care for acute migraine treatment, considering both direct and indirect costs.
Explore the potential benefits of Zavegepant nasal spray in other headache disorders, such as cluster headaches or tension-type headaches, to broaden the understanding of its therapeutic potential in various headache conditions.
By addressing these recommendations in future trials and secondary studies, we can further enhance our understanding of Zavegepant nasal spray effectiveness and safety profile in the acute treatment of migraine and potentially improve patient outcomes.
14. Conclusion
This meta-analysis substantiates the efficacy of Zavegepant nasal spray in the acute treatment of migraine, demonstrating significant improvements in pain freedom at 2 hours, freedom from the most bothersome symptom at 2 hours, and sustained pain freedom between 2 and 48 hours. The inconclusive results regarding pain relapse between 2 and 48 hours call for further investigation. Nevertheless, the overall findings indicate that Zavegepant nasal spray could be a promising option for the management of acute migraine episodes. Zavegepant nasal spray has demonstrated promising results in the acute treatment of migraine. Nasal administration offers several advantages over oral formulations, including a rapid onset of action, improved patient compliance, bypassing first-pass metabolism, and potential benefits for specific patient populations. Further research is warranted to elucidate the effect of Zavegepant on pain relapse and to assess its safety and tolerability, ultimately contributing to a comprehensive understanding of its therapeutic potential in migraine management.
Author contributions
Conceptualization: Muhammad Waqas, Faizan Ur Rehman Ansari, Anam Nazir, Manish KC.
Data curation: Muhammad Waqas, Anam Nazir, Khadija Saleem Raza Hussain.
Formal analysis: Azza Sarfraz.
Investigation: Anam Nazir, Muzna Sarfraz.
Methodology: Faizan Ur Rehman Ansari, Zouina Sarfraz, Azza Sarfraz, Muzna Sarfraz.
Resources: Muhammad Waqas, Anam Nazir.
Supervision: Faizan Ur Rehman Ansari, Manish KC.
Visualization: Khadija Saleem Raza Hussain, Zouina Sarfraz, Manish KC.
Writing – original draft: Muhammad Waqas, Faizan Ur Rehman Ansari, Anam Nazir, Khadija Saleem Raza Hussain, Zouina Sarfraz, Azza Sarfraz, Muzna Sarfraz, Manish KC.
Writing – review & editing: Muhammad Waqas, Faizan Ur Rehman Ansari, Anam Nazir, Khadija Saleem Raza Hussain, Zouina Sarfraz, Azza Sarfraz, Muzna Sarfraz, Manish KC.
Supplementary Material
Abbreviations:
- CGRP
- calcitonin gene-related peptide
- CI
- confidence interval
- MBS
- most bothersome symptom
- NCT
- National Clinical Trial
- OR
- odds ratio
- PRO
- patient reported outcome
- RCTs
- randomized controlled trials
- RevMan
- Review Manager
- ROB
- risk of bias
- ROBINS-I
- risk of bias in non-randomized studies of interventions
No ethical approval was required as only secondary clinical data was used.
The authors have no funding and conflicts of interest to disclose.
All data generated or analyzed during this study are included in this published article [and its supplementary information files].
Supplemental Digital Content is available for this article.
How to cite this article: Waqas M, Ansari FUR, Nazir A, Hussain KSR, Sarfraz Z, Sarfraz A, Sarfraz M, KC M. Zavegepant nasal spray for the acute treatment of migraine: A meta analysis. Medicine 2023;102:43(e35632).
Contributor Information
Muhammad Waqas, Email: mwaqasmalik694@gmail.com.
Faizan Ur Rehman Ansari, Email: Faizansalam89@gmail.com.
Anam Nazir, Email: anam.nazir44@gmail.com.
Khadija Saleem Raza Hussain, Email: romeosuperwoman@gmail.com.
Zouina Sarfraz, Email: sarfrazmuzna@gmail.com.
Azza Sarfraz, Email: sarfrazmuzna@gmail.com.
Muzna Sarfraz, Email: sarfrazmuzna@gmail.com.
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