Unsatisfactory Response to Acute Medications Does Not Affect the Medication Overuse Headache Development in Pediatric Chronic Migraine

Unsatisfactory Response to Acute Medications Does Not Affect the Medication Overuse Headache Development in Pediatric Chronic Migraine | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Unsatisfactory Response to Acute Medications Does Not Affect the Medication Overuse Headache Development in Pediatric Chronic Migraine Ilaria Frattale, Michela Ada Noris Ferilli, Fabiana Ursitti, Giorgia Sforza, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4000238/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 22 Apr, 2024 Read the published version in The Journal of Headache and Pain → Version 1 posted 7 You are reading this latest preprint version Abstract Background: Chronic migraine (CM) affects 2 to 4% of paediatric patients and has a significant impact on their quality of life. While in adults CM is very often associated to medication overuse headache (MOH), in children MOH prevalence is far lower. Suboptimal response to attack therapies may lead to their reduced assumption, thus preventing MOH development in children and adolescents. The main aim of our study was to verify whether among CM patients those with a poor response to the attack therapy showed a lower frequency of MOH, compared to those responding to the analgesic drugs. We also checked whether patients receiving prophylactic therapy had a better response to rescue drugs. Lastly, we investigated the frequency of psychiatric comorbidities between responders and non-responders. Methods: We retrospectively analysed clinical data of all chronic paediatric migraineurs under the age of 18 referred to the Headache Centre at Bambino Gesù Children Hospital June 2021 and February 2023. As primary endpoints, we evaluated: 1) unresponsiveness to acute medication in the whole population, and 2) the frequency of MOH in patients responder and non-responder to abortive drugs. As secondary endpoints, we evaluated the impact of preventive treatment and psychiatric comorbidities on the responsiveness to acute medication. Results: Seventy patients with CM were assessed during the chosen period. Paracetamol was tried by 41 patients (58.5%), NSAIDs by 56 patients (80.0%), and triptans by 1 patient (1.4%). Fifty-one participants (73%) were resistant to the abortive treatment. The presence of MOH was detected in 27.1% of the whole populations. Regarding our primary aim, MOH was diagnosed in 29% of resistant patients and 22% of responders (p >0.05). Preventative treatment was prescribed to all patients. After 3 months of preventive pharmacological therapy, 65.4% of patients who did not respond to acute medications achieved a response, while 34.6% of patients who were resistant kept not responding (p < 0.05). Among the patients who responded to acute medication, 69% also responded to prophylactic therapy (p < 0.05). Psychiatric comorbidities were detected in 68.6% of patients, with no difference between responders and non-responders (72.2% vs. 67.3%; p=0.05). Conclusions: Although in pediatric CM unresponsiveness to abortive drugs is highly prevalent, it does not represent a protective factor for MOH. Moreover, responsiveness to abortive drugs is improved by pharmacological preventative treatment and it is not affected by concomitant psychiatric comorbidities. childhood adolescents chronic migraine medication overuse headache acute treatment Figures Figure 1 Introduction Migraine is the primary cause of pain in childhood and its frequency increases with age, overtaking 20% in adolescence ( 1 ). It is a condition that can fluctuate in frequency, severity, and disability throughout life. The transition between episodic and chronic forms is possible ( 2 – 5 ), and the origin of this modification is not fully understood ( 6 ). Approximately 2 to 4% of pediatric migraine sufferers experience chronic migraine (CM) ( 7 – 9 ). According to the ICHD3 criteria, CM is defined by the presence of at least 15 headache days for a minimum of 3 months with at least 8 migraine days each month ( 10 ). Chronic headache can negatively impact one's quality of life and ability to complete routine school and sports activities, as well as maintain social relationships ( 11 ). Central sensitization changes can be caused by the increased use of painkillers, which can decrease the effectiveness of acute medications ( 12 – 15 ). This phenomenon may be responsible of frequent rescue drug intakes, MOH development, and migraine chronification ( 6 , 16 – 18 ). Response to acute treatment, which includes NSAIDs, triptans, and combinations, is defined as pain relief within 2 hours and well-being state lasting at least 24 hours ( 19 ). Oral formulation is the most used by migraineurs with a 2-hour pain free rate from 19 to 40% ( 20 , 21 ), while the subcutaneous administration (e. g. triptans) leads to pain free between 60 and 65% of cases ( 22 ). Failed response to treatment can be caused by factors such as late intake, inadequate dosage, and formulations with inadequate absorption ( 23 ). A lower response to painkillers is observed during the chronic course of migraine ( 6 ). Obesity and neuropsychiatric comorbidities are among the concomitant conditions that could lead to resistance to rescue drugs ( 24 ). Pediatric studies have indicated that MOH is less prevalent in children and adolescents than in adult patients ( 25 – 29 ). Although the reason is not known, factors related to brain development and the progression of migraine could explain the different prevalence of MOH in pediatric migraineurs and adulthood ( 28 ). The hypothesis can be made that pediatric patients with CM may scarcely respond to pharmacological treatments for the acute attack, which could discourage them from using analgesic drugs frequently. If this were true, we would expect a lower MOH prevalence in patients who do not respond than in those responding to rescue therapy. The primary aims of our study were: 1) to calculate the frequency of pediatric patients with CM who exhibited resistance to the attack therapies, and 2) to investigate whether MOH prevalence was different between responders and non-responders to the analgesic drugs. As secondary aims, we examined: 1) the impact of prophylactic treatment on the response to acute treatment and 2) the different frequency of psychiatric comorbidities between responders and non-responders to rescue therapy. Methods Patients We retrospectively analysed clinical data of all patients affected by CM who attended the Headache Centre at Bambino Gesù Children Hospital in the period between June 2021 and February 2023. Data were collected for patients between the ages of 6 and 17 during the initial visit and at a second follow-up visit. For diagnosis of CM, we referred to ICHD3 criteria ( 10 ). We analyzed demographic characteristics, including sex, age at onset of migraine, age at CM onset, frequency of the attacks, MOH diagnosis, and response to acute medications at baseline and after 3 months of preventive treatment. Neuropsychiatric comorbidities were referred by the children’s parents during the first attendance evaluation. As acute medications, paracetamol, nonsteroidal anti-inflammatory drugs (NSAIDs) and triptans were considered separately. A patient was defined as not responder to attack therapy when he did not respond to paracetamol, an NSAID, and a triptan. We assumed that, due to local legislative reasons and patients’ age, the prescription of triptans was not common. For this reason, we also considered as not responder those who had no response to paracetamol and two NSAIDs. Statistical analysis Statistical analysis was conducted using SPPS version 22.0 and consisted of three steps. The initial step involved a descriptive analysis that reported the differences between the responders and non-responders to analgesic drugs. In particular, for the categorical variables (sex, response or not to prophylactic therapy, and the presence or absence of psychiatric comorbidities) we considered the χ2 test, while for the ordinary variables (age) we used the analysis of variance (ANOVA). The second step was a bivariate analysis to study how each variable, considered individually, correlated with either response or resistance to attack therapy. Different statistical tests were used depending on the nature of the covariates and the response. For ordinal categorical variables, we used the Mann-Whitney U-test, the Kruskal-Wallis test and the Spearman’s Rho. For the numeric variables, we transformed the response using the log scale ratio and considered the t-test, ANOVA, and Spearman's Rho. The individual tests in the bivariate analysis did not consider the contemporary effect of other covariates. The third step was a multivariate analysis where all the variables that in the bivariate analysis showed a p-value ≤ 0.2 in determining response or resistance to acute therapy were included. A generalized linear model (GLM) with cumulative link and proportional odds assumption was utilized for multivariate analysis. A p-value being ≤ 0.05 was deemed significant. The parents of the participants provided written informed consent. The study was approved by the Ethics Committee of Bambino Gesù Children Hospital. Results In the considered period of time considered, 1680 children and adolescents were visited at our Headache Center. According to ICHD 3 criteria, 81 patients (4.8%) were diagnosed with CM. Eleven patients were excluded from further analysis since we did not have enough data on the use of therapy for the attack (untried or assumed at inadequate dosages). The analysed population included 70 patients (58 females and 12 males) with an average age at the time of the first visit of 14.2 ± 2.4 years. Demographic features of the sample are summarized in table 1. The average age of migraine onset was 11.2 ± 3.2 years, while the average age of CM onset was 13.6 ± 2.3 years. Migraine lasted an average of 2.4 years from its onset before becoming chronic. Before having CM, 87% of patients had a high-frequency episodic migraine (EM) (more than 5 attacks per month). In 28.5% of cases, a prophylactic treatment had been tried and resulted ineffective. Before arriving at our center, 41 out of 70 patients had tried paracetamol (58.6%), 56 NSAIDs (80%), and only 1 triptans (1.4%). Fifty-one participants (73%) were resistant to the attack treatment, while 19 (27%) were responsive. Response to acute treatment was independent of the drug (Figs. 1). Response or resistance to the attack therapy did not depend on the age at migraine onset (mean age: 11.2 vs. 11.4 years; p > 0.05) and at CM onset (mean age: 13.8 vs. 13.5 years; p > 0.05), and the duration of the disease (32.3 vs. 27.5 months; p > 0.05). Among the total subjects (n = 70), in 19 (27.1%) of cases, there was a concomitant presence of MOH. In these patients, an average of 23.5 doses of rescue medications per month were assumed. MOH prevalence was similar among non-responders and responders (29% vs. 22%; p > 0.05). All patients were given prophylactic pharmacological therapy, and the response was confirmed at a follow-up visit three months after the start. Twelve patients did not assume the prescribed therapy or suspended it too early (within a month). A decrease in headache days per month ≥ 50% was observed in 58% (34/58) of patients who received prophylaxis. After prophylaxis, the prevalence of patients responding to the analgesic drugs increased to 71.4% (41/58), while resistant patients decreased to 28.6% (17/58). More in detail, 65.4% of subjects who failed to respond to attack therapy before initiating prophylaxis achieved a response after 3 months of preventive pharmacological therapy. The remaining resistant patients (34.6%) kept not responding to the drugs for the attack (p < 0.05). Among the patients who responded to the attack therapy, 69% simultaneously responded to the prophylactic therapy, while 31% did not experience a significant change in headache days per month (p < 0.01). The bivariate analysis identified only prophylactic therapy as a factor associated with response to attack therapy (R 0.9; C.I. 0.7–0.95; p < 0.05). Psychiatric comorbidities were referred in 48 of patients (69%). Anxiety and depressive disorders were the most prevalent psychiatric conditions. The frequency of psychiatric comorbidities did not differ significantly between responders and non-responders to analgesic drugs (72.2% vs. 67.3%; p = 0.05). Discussion Resistance to acute treatment is an important issue in both paediatric and adult patients with migraine. In this context, the most significant results of our study in a paediatric cohort of CM patients were as follows: 1. Acute medications were ineffective in most CM patients. 2. MOH prevalence was similar in both responders and non-responders, suggesting that failure to abort medication does not affect MOH development. 3. After three months of preventative treatment, most patients, especially those with a good outcome after prophylaxis, returned to respond to acute medication. 4. Psychiatric comorbidities did not influence response to acute medication 1.Poor response to attack therapy in children and adolescents with CM We found that acute medications were ineffective for most CM patients. The result confirms our hypothesis that CM patients have a decreased response to attack therapy. Whether a poor response to acute therapy is a risk factor for the development of CM rather than a consequence of migraine severity still represents a debated question (6). In patients with episodic migraine, suboptimal response to acute treatment was associated to a risk of developing CM within one year, independently of other migraine features, such as disability and frequency of the attacks (23). Acute treatment failure can result in more frequent and longer attacks and greater disability, which can lead to the onset of CM (6,12–15). In this view, more effective acute treatments should decrease the possibility CM development. In CM patients, resistance to acute drugs often involve multiple treatments (23). Our findings, showing that non-responders are resistant to at least two categories of drugs including paracetamol, NSAIDs and triptans, agree with previous results. The weak response to multiple rescue drugs in CM suggests that it is the disease severity to be mainly responsible of the resistance to analgesic drugs (6). Migraine progression leads to central sensitization, which on its turn could reduce the response to rescue drugs (6). Not only the poor response to attack therapy but also the overuse of rescue drugs is a risk factor for migraine progression and the onset of MOH (16–18,23,30,31). 2. Might poor response to attack therapy reduce the risk of MOH? A primary aim of this study was to investigate whether the poor response to analgesic drugs could contribute to the lower prevalence of MOH in children and adolescents, as compared to adults (25). Indeed, patients with suboptimal response to acute therapy may be discouraged from using it frequently. Compared to the adult population with chronic headache in which MOH has a prevalence of 64% (32), in pediatric age MOH is far rarer, ranging from 20 to 50% of chronic patients (27–29). Since the possibility of MOH development raises with increasing age, the parental control over drug intake could partly explain the difference between children and adulthood (33). MOH pathophysiology is very complex and not fully understood. Beyond the amount of analgesic drug intake, other factors, such as medication effects (34), genetics factors (35) and headache-specific pain pathways (36), are involved. In our sample, MOH was diagnosed in 25% of patients with a similar prevalence in both responders and non-responders. This result did not confirm our initial hypothesis of a key role played by the poor response of analgesic drugs in explaining the rather low prevalence of MOH in children compared to adulthood. Therefore, we can conclude that in pediatric age the unresponsiveness to the rescue therapy does not have a protective role for MOH development. One may wonder why non-responders keep assuming drugs which, however, do not help them in reducing pain. Though not completely known, this behaviour suggests the possibility of an addictive psychopathological profiles of either the patient or her/his parents who administer the drug (37,38). 3. Are prophylactic therapies useful in pediatric migraine? We found that more than 70% of patients receiving prophylactic therapy experienced a significant improvement in response to acute medication. Among them, 69% reported a reduction of more than 50% in headache days per month, compared to the three months before treatment. In children and adolescents, the use of a pharmacological prophylactic treatments is not so largely accepted as for adults. First, there can be some legal limitations. In 2014, topiramate was approved by the food and drug administration for the prophylactic treatment of migraine in children over 12 years on the base of robust clinical results (39,40). Unfortunately, there are only limited data for other drugs which are not licenced for pediatrc age (33,41–45). As for monoclonal antibodies and gepants, they are still object of clinical trials and cannot be prescribed. Second, the usefulness of the prophylactic pharmacological treatments in children and adolescents has been challenged by the CHAMP study, which failed in showing a superiority of either topiramate or amitriptyline over placebo (41). Considering the possible side effects of prophylactic drugs and the high placebo efficacy rate, Powers et al. suggested that psychological treatments should be preferred to medications (41). Although our study was not designed to investigate the efficacy of pharmacological prophylactic treatments and we did not consider a control group with placebo, more than half of our patients undergone prophylaxis showed a significant reduction in headache days per month. However, what is most noteworthy within the present results is that more than two third of our patients improved their response to analgesic drugs after prophylaxis. Though needing confirmation in appropriately designed trial, our present findings suggest that the response to acute therapy should be considered in future clinical studies on migraine prophylaxis in children and adolescents. 4. The effect of psychiatric comorbidities on the response to acute therapy A nxiety and depression are show a high prevalence in children and adolescents with migraine (46,47). These disturbances may even predict poor response to acute and preventive therapy and greater disability (48,49). On the other hand, headache chronification may lead to reduced quality of life and disability, which can be represent factors for the onset of mood disorders (50). From this point of view, the possibility that neuropsychiatric disturbances may have a role in determining the response to the acute treatment is conceivable. In our study, psychiatric comorbidities were present in almost 70% of patients, who showed the same poor response to analgesic drugs as those without psychiatric symptoms. In conclusion, therefore, our data suggest that in paediatric patients with chronic headache the response to analgesic drug is not affected by neuropsychiatric comorbidities. Limitations Our study has some limitations mainly due to its retrospective nature. First, since most patients came to our attention already showing a chronic migraine, we do not have detailed information about the previous migraine time course. Second, for most patients we do not know their response to acute medications before their migraine chronification. Of course, this prevents us to know with certainty whether the poor response to rescue drugs is due to the chronification mechanisms or it is independent of them. Third, in our patients the neuropsychiatric comorbidities were diagnosed on the base of what was referred by the patients and their parents. Further studies, using validated tools for the diagnosis of psychiatric disturbances are needed to define the effect of them on the response to acute medications. Conclusion In conclusion, our results suggest that the poor response to analgesic drugs, observed in our patients with CM, does no explain the rather low prevalence of MOH. Moreover, we found that using a prophylactic treatment may improve the therapeutic response to acute medication, thus reducing the disability related to the migraine attack. Lastly, psychiatric comorbidities, though to be considered in the whole assessment of CM patients, do not affect the response to acute therapy. Declarations Funding: This work was supported by the Italian Ministry of Health with Current Research funds and FINALIZED RESEARCH Grant 2019 (code: GR-2019-12369766). Conflicts of Interest: "The authors declare no conflict of interest." Clinical Trial Number : not available Data Availability declaration: The data that support the findings of this study are not openly available due to reasons of sensitivity and are available from the corresponding author upon reasonable request. Data are located in controlled access data storage at Bambino Gesù Children’s Hospital, Rome. Author Contribution Author Contributions: Conceptualization, L.P. and M.V.; Methodology, M.A.N.F.; Validation, L.P and M.V; Writing – Original Draft Preparation, I.F.; Writing – Review & Editing, L.P. and M.V; Figure and table: F.U.; Data setting: G.M; M.P.C. and S.T, Visualization L.P.; M.V, L.M.;M.A.N.F.; G.M.;G.S.; F.U.; I.F.; S.T.; M.P.C.; Supervision, L.P. References Abu‐Arafeh I, Razak S, Sivaraman B, Graham C. Prevalence of headache and migraine in children and adolescents: a systematic review of population‐based studies. Develop Med Child Neuro. dicembre 2010;52(12):1088–97. 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Demographic Characteristics of n=70 patients in the analysed period Cite Share Download PDF Status: Published Journal Publication published 22 Apr, 2024 Read the published version in The Journal of Headache and Pain → Version 1 posted Editorial decision: Revision requested 23 Mar, 2024 Reviews received at journal 21 Mar, 2024 Reviewers agreed at journal 10 Mar, 2024 Reviewers invited by journal 10 Mar, 2024 Editor assigned by journal 05 Mar, 2024 Submission checks completed at journal 05 Mar, 2024 First submitted to journal 29 Feb, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4000238","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":276454814,"identity":"816185a2-4f48-461b-84c0-07ab88744ef3","order_by":0,"name":"Ilaria Frattale","email":"","orcid":"","institution":"Tor Vergata University of Rome","correspondingAuthor":false,"prefix":"","firstName":"Ilaria","middleName":"","lastName":"Frattale","suffix":""},{"id":276454815,"identity":"ccdbaae4-3a29-4272-8c1c-3906ffdc0d96","order_by":1,"name":"Michela Ada Noris Ferilli","email":"","orcid":"","institution":"Policlinico Tor Vergata Foundation Hospital","correspondingAuthor":false,"prefix":"","firstName":"Michela","middleName":"Ada Noris","lastName":"Ferilli","suffix":""},{"id":276454816,"identity":"e6605b95-f8ed-4588-8123-6f4b2d3df1fa","order_by":2,"name":"Fabiana Ursitti","email":"","orcid":"","institution":"Bambino Gesù Children’ s Hospital, IRCCS","correspondingAuthor":false,"prefix":"","firstName":"Fabiana","middleName":"","lastName":"Ursitti","suffix":""},{"id":276454817,"identity":"44c64da4-0ce1-4177-ad82-ab6642f3ea46","order_by":3,"name":"Giorgia Sforza","email":"","orcid":"","institution":"Bambino Gesù Children’ s Hospital, IRCCS","correspondingAuthor":false,"prefix":"","firstName":"Giorgia","middleName":"","lastName":"Sforza","suffix":""},{"id":276454818,"identity":"3c083078-7290-4061-a25a-d80871c9f936","order_by":4,"name":"Gabriele Monte","email":"","orcid":"","institution":"Bambino Gesù Children’ s Hospital, IRCCS","correspondingAuthor":false,"prefix":"","firstName":"Gabriele","middleName":"","lastName":"Monte","suffix":""},{"id":276454819,"identity":"7816e3ac-1c96-4ada-a1ba-8e2beab350c7","order_by":5,"name":"Martina Proietti Checchi","email":"","orcid":"","institution":"Bambino Gesù Children’ s Hospital, IRCCS","correspondingAuthor":false,"prefix":"","firstName":"Martina","middleName":"Proietti","lastName":"Checchi","suffix":""},{"id":276454820,"identity":"ae792f2e-9dc3-4fdc-9933-18a61daf5c6d","order_by":6,"name":"Samuela Tarantino","email":"","orcid":"","institution":"Bambino Gesù Children’ s Hospital, IRCCS","correspondingAuthor":false,"prefix":"","firstName":"Samuela","middleName":"","lastName":"Tarantino","suffix":""},{"id":276454821,"identity":"787ac584-8c51-4dfa-be1b-c8f57fb3d8b8","order_by":7,"name":"Luigi Mazzone","email":"","orcid":"","institution":"Tor Vergata University of Rome","correspondingAuthor":false,"prefix":"","firstName":"Luigi","middleName":"","lastName":"Mazzone","suffix":""},{"id":276454822,"identity":"ca327004-55e8-46c2-b781-3e3a376d6f91","order_by":8,"name":"Massimiliano Valeriani","email":"data:image/png;base64,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","orcid":"","institution":"Bambino Gesù Children’ s Hospital, IRCCS","correspondingAuthor":true,"prefix":"","firstName":"Massimiliano","middleName":"","lastName":"Valeriani","suffix":""},{"id":276454823,"identity":"ab2479d8-f8b1-4ee3-a688-477c1efc6f73","order_by":9,"name":"Laura Papetti","email":"","orcid":"","institution":"Bambino Gesù Children’ s Hospital, IRCCS","correspondingAuthor":false,"prefix":"","firstName":"Laura","middleName":"","lastName":"Papetti","suffix":""}],"badges":[],"createdAt":"2024-02-29 14:49:59","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4000238/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4000238/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s10194-024-01766-7","type":"published","date":"2024-04-23T00:48:16+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":52195634,"identity":"9a7a9ffc-afbd-430c-88ca-2afd6f9a242e","added_by":"auto","created_at":"2024-03-07 19:53:40","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":55390,"visible":true,"origin":"","legend":"\u003cp\u003eAcute medications response rate at baseline and after 3-months-preventative treatment\u003c/p\u003e","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4000238/v1/f03126ab71615ab5583e46f0.jpg"},{"id":55121509,"identity":"3990a2a8-eeca-4eda-a0a0-c4b92521fcbe","added_by":"auto","created_at":"2024-04-23 00:48:21","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":298419,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4000238/v1/cee83d82-d132-4a32-b1dc-862edf9f5039.pdf"},{"id":52195633,"identity":"74d25577-c028-4dce-a822-a2515e80aaf6","added_by":"auto","created_at":"2024-03-07 19:53:40","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":14750,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eTable 1. \u003c/strong\u003eDemographic Characteristics of n=70 patients in the analysed period\u003c/p\u003e","description":"","filename":"table1.docx","url":"https://assets-eu.researchsquare.com/files/rs-4000238/v1/04740965591201a6a9eb02f9.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"\u003cp\u003eUnsatisfactory Response to Acute Medications Does Not Affect the Medication Overuse Headache Development in Pediatric Chronic Migraine\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eMigraine is the primary cause of pain in childhood and its frequency increases with age, overtaking 20% in adolescence (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). It is a condition that can fluctuate in frequency, severity, and disability throughout life. The transition between episodic and chronic forms is possible (\u003cspan additionalcitationids=\"CR3 CR4\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e), and the origin of this modification is not fully understood (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eApproximately 2 to 4% of pediatric migraine sufferers experience chronic migraine (CM) (\u003cspan additionalcitationids=\"CR8\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). According to the ICHD3 criteria, CM is defined by the presence of at least 15 headache days for a minimum of 3 months with at least 8 migraine days each month (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). Chronic headache can negatively impact one's quality of life and ability to complete routine school and sports activities, as well as maintain social relationships (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eCentral sensitization changes can be caused by the increased use of painkillers, which can decrease the effectiveness of acute medications (\u003cspan additionalcitationids=\"CR13 CR14\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). This phenomenon may be responsible of frequent rescue drug intakes, MOH development, and migraine chronification (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan additionalcitationids=\"CR17\" citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eResponse to acute treatment, which includes NSAIDs, triptans, and combinations, is defined as pain relief within 2 hours and well-being state lasting at least 24 hours (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e). Oral formulation is the most used by migraineurs with a 2-hour pain free rate from 19 to 40% (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e), while the subcutaneous administration (e. g. triptans) leads to pain free between 60 and 65% of cases (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e). Failed response to treatment can be caused by factors such as late intake, inadequate dosage, and formulations with inadequate absorption (\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e). A lower response to painkillers is observed during the chronic course of migraine (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). Obesity and neuropsychiatric comorbidities are among the concomitant conditions that could lead to resistance to rescue drugs (\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e).\u003c/p\u003e \u003cp\u003ePediatric studies have indicated that MOH is less prevalent in children and adolescents than in adult patients (\u003cspan additionalcitationids=\"CR26 CR27 CR28\" citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e). Although the reason is not known, factors related to brain development and the progression of migraine could explain the different prevalence of MOH in pediatric migraineurs and adulthood (\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e). The hypothesis can be made that pediatric patients with CM may scarcely respond to pharmacological treatments for the acute attack, which could discourage them from using analgesic drugs frequently. If this were true, we would expect a lower MOH prevalence in patients who do not respond than in those responding to rescue therapy.\u003c/p\u003e \u003cp\u003eThe primary aims of our study were: 1) to calculate the frequency of pediatric patients with CM who exhibited resistance to the attack therapies, and 2) to investigate whether MOH prevalence was different between responders and non-responders to the analgesic drugs. As secondary aims, we examined: 1) the impact of prophylactic treatment on the response to acute treatment and 2) the different frequency of psychiatric comorbidities between responders and non-responders to rescue therapy.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e \u003cem\u003ePatients\u003c/em\u003e \u003c/p\u003e \u003cp\u003eWe retrospectively analysed clinical data of all patients affected by CM who attended the Headache Centre at Bambino Ges\u0026ugrave; Children Hospital in the period between June 2021 and February 2023. Data were collected for patients between the ages of 6 and 17 during the initial visit and at a second follow-up visit. For diagnosis of CM, we referred to ICHD3 criteria (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eWe analyzed demographic characteristics, including sex, age at onset of migraine, age at CM onset, frequency of the attacks, MOH diagnosis, and response to acute medications at baseline and after 3 months of preventive treatment. Neuropsychiatric comorbidities were referred by the children\u0026rsquo;s parents during the first attendance evaluation.\u003c/p\u003e \u003cp\u003eAs acute medications, paracetamol, nonsteroidal anti-inflammatory drugs (NSAIDs) and triptans were considered separately. A patient was defined as not responder to attack therapy when he did not respond to paracetamol, an NSAID, and a triptan. We assumed that, due to local legislative reasons and patients\u0026rsquo; age, the prescription of triptans was not common. For this reason, we also considered as not responder those who had no response to paracetamol and two NSAIDs.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eStatistical analysis was conducted using SPPS version 22.0 and consisted of three steps.\u003c/p\u003e \u003cp\u003eThe initial step involved a descriptive analysis that reported the differences between the responders and non-responders to analgesic drugs. In particular, for the categorical variables (sex, response or not to prophylactic therapy, and the presence or absence of psychiatric comorbidities) we considered the χ2 test, while for the ordinary variables (age) we used the analysis of variance (ANOVA).\u003c/p\u003e \u003cp\u003eThe second step was a bivariate analysis to study how each variable, considered individually, correlated with either response or resistance to attack therapy. Different statistical tests were used depending on the nature of the covariates and the response. For ordinal categorical variables, we used the Mann-Whitney U-test, the Kruskal-Wallis test and the Spearman\u0026rsquo;s Rho. For the numeric variables, we transformed the response using the log scale ratio and considered the t-test, ANOVA, and Spearman's Rho. The individual tests in the bivariate analysis did not consider the contemporary effect of other covariates.\u003c/p\u003e \u003cp\u003eThe third step was a multivariate analysis where all the variables that in the bivariate analysis showed a p-value\u0026thinsp;\u0026le;\u0026thinsp;0.2 in determining response or resistance to acute therapy were included. A generalized linear model (GLM) with cumulative link and proportional odds assumption was utilized for multivariate analysis. A p-value being \u0026le;\u0026thinsp;0.05 was deemed significant.\u003c/p\u003e \u003cp\u003e The parents of the participants provided written informed consent. The study was approved by the Ethics Committee of Bambino Ges\u0026ugrave; Children Hospital.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eIn the considered period of time considered, 1680 children and adolescents were visited at our Headache Center. According to ICHD 3 criteria, 81 patients (4.8%) were diagnosed with CM. Eleven patients were excluded from further analysis since we did not have enough data on the use of therapy for the attack (untried or assumed at inadequate dosages). The analysed population included 70 patients (58 females and 12 males) with an average age at the time of the first visit of 14.2 \u0026plusmn; 2.4 years. Demographic features of the sample are summarized in table 1.\u003c/p\u003e \u003cp\u003eThe average age of migraine onset was 11.2 \u0026plusmn; 3.2 years, while the average age of CM onset was 13.6 \u0026plusmn; 2.3 years. Migraine lasted an average of 2.4 years from its onset before becoming chronic. Before having CM, 87% of patients had a high-frequency episodic migraine (EM) (more than 5 attacks per month). In 28.5% of cases, a prophylactic treatment had been tried and resulted ineffective.\u003c/p\u003e \u003cp\u003eBefore arriving at our center, 41 out of 70 patients had tried paracetamol (58.6%), 56 NSAIDs (80%), and only 1 triptans (1.4%).\u003c/p\u003e \u003cp\u003eFifty-one participants (73%) were resistant to the attack treatment, while 19 (27%) were responsive. Response to acute treatment was independent of the drug (Figs.\u0026nbsp;1).\u003c/p\u003e \u003cp\u003eResponse or resistance to the attack therapy did not depend on the age at migraine onset (mean age: 11.2 vs. 11.4 years; p\u0026thinsp;\u0026gt;\u0026thinsp;0.05) and at CM onset (mean age: 13.8 vs. 13.5 years; p\u0026thinsp;\u0026gt;\u0026thinsp;0.05), and the duration of the disease (32.3 vs. 27.5 months; p\u0026thinsp;\u0026gt;\u0026thinsp;0.05).\u003c/p\u003e \u003cp\u003eAmong the total subjects (n\u0026thinsp;=\u0026thinsp;70), in 19 (27.1%) of cases, there was a concomitant presence of MOH. In these patients, an average of 23.5 doses of rescue medications per month were assumed. MOH prevalence was similar among non-responders and responders (29% vs. 22%; p\u0026thinsp;\u0026gt;\u0026thinsp;0.05).\u003c/p\u003e \u003cp\u003eAll patients were given prophylactic pharmacological therapy, and the response was confirmed at a follow-up visit three months after the start. Twelve patients did not assume the prescribed therapy or suspended it too early (within a month). A decrease in headache days per month\u0026thinsp;\u0026ge;\u0026thinsp;50% was observed in 58% (34/58) of patients who received prophylaxis. After prophylaxis, the prevalence of patients responding to the analgesic drugs increased to 71.4% (41/58), while resistant patients decreased to 28.6% (17/58). More in detail, 65.4% of subjects who failed to respond to attack therapy before initiating prophylaxis achieved a response after 3 months of preventive pharmacological therapy. The remaining resistant patients (34.6%) kept not responding to the drugs for the attack (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05). Among the patients who responded to the attack therapy, 69% simultaneously responded to the prophylactic therapy, while 31% did not experience a significant change in headache days per month (p\u0026thinsp;\u0026lt;\u0026thinsp;0.01). The bivariate analysis identified only prophylactic therapy as a factor associated with response to attack therapy (R 0.9; C.I. 0.7\u0026ndash;0.95; p\u0026thinsp;\u0026lt;\u0026thinsp;0.05).\u003c/p\u003e \u003cp\u003ePsychiatric comorbidities were referred in 48 of patients (69%). Anxiety and depressive disorders were the most prevalent psychiatric conditions. The frequency of psychiatric comorbidities did not differ significantly between responders and non-responders to analgesic drugs (72.2% vs. 67.3%; p\u0026thinsp;=\u0026thinsp;0.05).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eResistance to acute treatment is an important issue in both paediatric and adult patients with migraine. \u0026nbsp;In this context, the most significant results of our study in a paediatric cohort of CM patients were as follows:\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e1. Acute medications were ineffective in most CM patients.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e2. MOH prevalence was similar in both responders and non-responders, suggesting that failure to abort medication does not affect MOH development.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e3. After three months of preventative treatment, most patients, especially those with a good outcome after prophylaxis, returned to respond to acute medication.\u003c/p\u003e\n\u003cp\u003e4. Psychiatric comorbidities did not influence response to acute medication\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cu\u003e1.Poor response to attack therapy in children and adolescents with CM\u0026nbsp;\u003c/u\u003e\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eWe found that acute medications were ineffective for most CM patients. The result confirms our hypothesis that CM patients have a decreased response to attack therapy. Whether a poor response to acute therapy is a risk factor for the development of CM rather than a consequence of migraine severity still represents a debated question (6). In patients with episodic migraine, suboptimal response to acute treatment was associated to a risk of developing CM within one year, independently of other migraine features, such as disability and frequency of the attacks (23). Acute treatment failure can result in more frequent and longer attacks and greater disability, which can lead to the onset of CM (6,12\u0026ndash;15). In this view, more effective acute treatments should decrease the possibility CM development. In CM patients, resistance to acute drugs often involve multiple treatments (23). \u0026nbsp;Our findings, showing that non-responders are resistant to at least two categories of drugs including paracetamol, NSAIDs and triptans, agree with previous results. The weak response to multiple rescue drugs in CM suggests that it is the disease severity to be mainly responsible of the resistance to analgesic drugs (6). Migraine progression leads to central sensitization, which on its turn could reduce the response to rescue drugs (6). Not only the poor response to attack therapy but also the overuse of rescue drugs is a risk factor for migraine progression and the onset of MOH (16\u0026ndash;18,23,30,31).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cu\u003e2. \u003cem\u003eMight poor response to attack therapy reduce the risk of MOH?\u003c/em\u003e\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eA primary aim of this study was to investigate whether the poor response to analgesic drugs could contribute to the lower prevalence of MOH in children and adolescents, as compared to adults\u0026nbsp;(25). Indeed, patients with suboptimal response to acute therapy may be discouraged from using it frequently. Compared to the adult population with chronic headache in which MOH has a prevalence of 64%\u0026nbsp;(32), in pediatric age MOH is far rarer, ranging from 20 to 50% of chronic patients\u0026nbsp;(27\u0026ndash;29). Since the possibility of MOH development raises with increasing age, the parental control over drug intake could partly explain the difference between children and adulthood\u0026nbsp;(33). MOH pathophysiology is very complex and not fully understood. Beyond the amount of analgesic drug intake, other factors, such as medication effects\u0026nbsp;(34), genetics factors\u0026nbsp;(35)\u0026nbsp;and headache-specific pain pathways\u0026nbsp;(36), are involved.\u003c/p\u003e\n\u003cp\u003eIn our sample, MOH was diagnosed in 25% of patients with a similar prevalence in both responders and non-responders. This result did not confirm our initial hypothesis of a key role played by the poor response of analgesic drugs in explaining the rather low prevalence of MOH in children compared to adulthood. Therefore, we can conclude that in pediatric age the unresponsiveness to the rescue therapy does not have a protective role for MOH development.\u003c/p\u003e\n\u003cp\u003eOne may wonder why non-responders keep assuming drugs which, however, do not help them in reducing pain. Though not completely known, this behaviour suggests the possibility of an addictive psychopathological profiles of either the patient or her/his parents who administer the drug (37,38).\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cu\u003e3.\u003c/u\u003e\u003c/em\u003e \u003cem\u003e\u003cu\u003eAre prophylactic therapies useful in pediatric migraine?\u003c/u\u003e\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eWe found that more than 70% of patients receiving prophylactic therapy experienced a significant improvement in response to acute medication. Among them, 69% reported a reduction of more than 50% in headache days per month, compared to the three months before treatment.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn children and adolescents, the use of a pharmacological prophylactic treatments is not so largely accepted as for adults. First, there can be some legal limitations. In 2014, topiramate was approved by the food and drug administration for the prophylactic treatment of migraine in children over 12 years on the base of robust clinical results\u0026nbsp;(39,40). Unfortunately, there are only limited data for other drugs which are not licenced for pediatrc age\u0026nbsp;(33,41\u0026ndash;45). As for monoclonal antibodies and gepants, they are still object of clinical trials and cannot be prescribed. Second, the usefulness of the prophylactic pharmacological treatments in children and adolescents has been challenged by the CHAMP study, which failed in showing a superiority of either topiramate or amitriptyline over placebo\u0026nbsp;(41). Considering the possible side effects of prophylactic drugs and the high placebo efficacy rate, Powers et al. suggested that psychological treatments should be preferred to medications\u0026nbsp;(41).\u003c/p\u003e\n\u003cp\u003eAlthough our study was not designed to investigate the efficacy of pharmacological prophylactic treatments and we did not consider a control group with placebo, more than half of our patients undergone prophylaxis showed a significant reduction in headache days per month. However, what is most noteworthy within the present results is that more than two third of our patients improved their response to analgesic drugs after prophylaxis. Though needing confirmation in appropriately designed trial, our present findings suggest that the response to acute therapy should be considered in future clinical studies on migraine prophylaxis in children and adolescents.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cu\u003e4.\u003c/u\u003e\u003c/em\u003e \u003cem\u003e\u003cu\u003eThe effect of psychiatric comorbidities on the response to acute therapy\u003c/u\u003e\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eA\u003c/u\u003enxiety and depression are show a high prevalence in children and adolescents with migraine (46,47). These disturbances may even predict poor response to acute and preventive therapy and greater disability (48,49). On the other hand, headache chronification may lead to reduced quality of life and disability, which can be represent factors for the onset of mood disorders (50). From this point of view, the possibility that neuropsychiatric disturbances may have a role in determining the response to the acute treatment is conceivable.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn our study, psychiatric comorbidities were present in almost 70% of patients, who showed the same poor response to analgesic drugs as those without psychiatric symptoms. In conclusion, therefore, our data suggest that in paediatric patients with chronic headache the response to analgesic drug is not affected by neuropsychiatric comorbidities.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eLimitations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOur study has some limitations mainly due to its retrospective nature. First, since most patients came to our attention already showing a chronic migraine, we do not have detailed information about the previous migraine time course. Second, for most patients we do not know their response to acute medications before their migraine chronification. Of course, this prevents us to know with certainty whether the poor response to rescue drugs is due to the chronification mechanisms or it is independent of them. \u0026nbsp;Third, in our patients the neuropsychiatric comorbidities were diagnosed on the base of what was referred by the patients and their parents. Further studies, using validated tools for the diagnosis of psychiatric disturbances are needed to define the effect of them on the response to acute medications.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn conclusion, our results suggest that the poor response to analgesic drugs, observed in our patients with CM, does no explain the rather low prevalence of MOH. Moreover, we found that using a prophylactic treatment may improve the therapeutic response to acute medication, thus reducing the disability related to the migraine attack. Lastly, psychiatric comorbidities, though to be considered in the whole assessment of CM patients, do not affect the response to acute therapy.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding:\u003c/strong\u003e This work was supported by the Italian Ministry of Health with Current Research funds and FINALIZED RESEARCH Grant 2019 (code: GR-2019-12369766).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of Interest:\u003c/strong\u003e\u0026nbsp; \u0026quot;The authors declare no conflict of interest.\u0026quot;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical Trial Number\u003c/strong\u003e: not available\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability declaration:\u0026nbsp;\u003c/strong\u003eThe data that support the findings of this study are not openly available due to reasons of sensitivity and are available from the corresponding author upon reasonable request. Data are located in controlled access data storage at Bambino Ges\u0026ugrave; Children\u0026rsquo;s Hospital, Rome.\u0026nbsp;\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eAuthor Contributions: Conceptualization, L.P. and M.V.; Methodology, M.A.N.F.; Validation, L.P and M.V; Writing \u0026ndash; Original Draft Preparation, I.F.; Writing \u0026ndash; Review \u0026amp; Editing, L.P. and M.V; Figure and table: F.U.; Data setting: G.M; M.P.C. and S.T, Visualization L.P.; M.V, L.M.;M.A.N.F.; G.M.;G.S.; F.U.; I.F.; S.T.; M.P.C.; Supervision, L.P.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eAbu‐Arafeh I, Razak S, Sivaraman B, Graham C. Prevalence of headache and migraine in children and adolescents: a systematic review of population‐based studies. Develop Med Child Neuro. dicembre 2010;52(12):1088\u0026ndash;97. \u003c/li\u003e\n\u003cli\u003eSerrano D, Lipton RB, Scher AI, Reed ML, Stewart WF, Adams AM, et al. 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Acta Neurologica Scandinavica. 29 gennaio 2009;50(1):109\u0026ndash;15. \u003c/li\u003e\n\u003cli\u003eSorge F, Simone RD, Marano E, Nolano M, Orefice G, Carrieri P. Flunarizine in Prophylaxis of Childhood Migraine: A Double-Blind, Placebo-Controlled, Crossover Study. Cephalalgia. marzo 1988;8(1):1\u0026ndash;6. \u003c/li\u003e\n\u003cli\u003eAshrafi MR, Salehi S, Malamiri RA, Heidari M, Hosseini SA, Samiei M, et al. Efficacy and Safety of Cinnarizine in the Prophylaxis of Migraine in Children: A Double-Blind Placebo-Controlled Randomized Trial. Pediatric Neurology. ottobre 2014;51(4):503\u0026ndash;8. \u003c/li\u003e\n\u003cli\u003eBattistella PA, Ruffilli R, Moro R, Fabiani M, Bertoli S, Antolini A, et al. A Placebo‐Controlled Crossover Trial of Nimodipine in Pediatric Migraine. Headache. aprile 1990;30(5):264\u0026ndash;8. \u003c/li\u003e\n\u003cli\u003eGesztelyi G. [Primary headache and depression]. Orv Hetil. 28 novembre 2004;145(48):2419\u0026ndash;24. \u003c/li\u003e\n\u003cli\u003eTarantino S, Papetti L, Di Stefano A, Messina V, Ursitti F, Ferilli MAN, et al. Anxiety, Depression, and Body Weight in Children and Adolescents With Migraine. Front Psychol. 28 ottobre 2020;11:530911. \u003c/li\u003e\n\u003cli\u003eGuidetti V, Galli F, Fabrizi P, Giannantoni A, Napoli L, Bruni O, et al. Headache and psychiatric comorbidity: clinical aspects and outcome in an 8-year follow-up study. Cephalalgia. settembre 1998;18(7):455\u0026ndash;62. \u003c/li\u003e\n\u003cli\u003eLant\u0026eacute;ri-Minet M, Radat F, Chautard MH, Lucas C. Anxiety and depression associated with migraine: Influence on migraine subjects\u0026rsquo; disability and quality of life, and acute migraine management. Pain. dicembre 2005;118(3):319\u0026ndash;26. \u003c/li\u003e\n\u003cli\u003eLewandowski AS, Palermo TM, Peterson CC. 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Headache. aprile 2006;46(4):656\u0026ndash;62. \u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"the-journal-of-headache-and-pain","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"tjhp","sideBox":"Learn more about [The Journal of Headache and Pain](https://thejournalofheadacheandpain.biomedcentral.com/)","snPcode":"10194","submissionUrl":"https://submission.nature.com/new-submission/10194/3","title":"The Journal of Headache and Pain","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"childhood, adolescents, chronic migraine, medication overuse headache, acute treatment","lastPublishedDoi":"10.21203/rs.3.rs-4000238/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4000238/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground: \u0026nbsp;\u003c/strong\u003eChronic migraine (CM) affects 2 to 4% of paediatric patients and has a significant impact on their quality of life. While in adults CM is very often associated to medication overuse headache (MOH), in children MOH prevalence is far lower. Suboptimal response to attack therapies may lead to their reduced assumption, thus preventing MOH development in children and adolescents.\u003c/p\u003e\n\u003cp\u003eThe main aim of our study was to verify whether among CM patients those with a poor response to the attack therapy showed a lower frequency of MOH, compared to those responding to the analgesic drugs. We also checked whether patients receiving prophylactic therapy had a better response to rescue drugs. Lastly, we investigated the frequency of psychiatric comorbidities between responders and non-responders.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods: \u0026nbsp;\u003c/strong\u003eWe retrospectively analysed clinical data of all chronic paediatric migraineurs under the age of 18 referred to the Headache Centre at Bambino Gesù Children Hospital June 2021 and February 2023. As primary endpoints, we evaluated: 1) unresponsiveness to acute medication in the whole population, and 2) the frequency of MOH in patients responder and non-responder to abortive drugs. As secondary endpoints, we evaluated the impact of preventive treatment and psychiatric comorbidities on the responsiveness to acute medication.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults: \u0026nbsp;\u003c/strong\u003eSeventy patients with CM were assessed during the chosen period. \u0026nbsp;Paracetamol was tried by 41 patients (58.5%), NSAIDs by 56 patients (80.0%), and triptans by 1 patient (1.4%). Fifty-one participants (73%) were resistant to the abortive treatment. The presence of MOH was detected in 27.1% of the whole populations. Regarding our primary aim, MOH was diagnosed in 29% of resistant patients and 22% of responders (p \u0026gt;0.05). Preventative treatment was prescribed to all patients. After 3 months of preventive pharmacological therapy, 65.4% of patients who did not respond to acute medications achieved a response, while 34.6% of patients who were resistant kept not responding (p \u0026lt; 0.05). Among the patients who responded to acute medication, 69% also responded to prophylactic therapy (p \u0026lt; 0.05). Psychiatric comorbidities were detected in 68.6% of patients, with no difference between responders and non-responders (72.2% vs. 67.3%; p=0.05).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions: \u0026nbsp;\u003c/strong\u003eAlthough\u003cstrong\u003e \u003c/strong\u003ein pediatric CM unresponsiveness to abortive drugs is highly prevalent, it does not represent a protective factor for MOH. Moreover, responsiveness to abortive drugs is improved by pharmacological preventative treatment and it is not affected by concomitant psychiatric comorbidities.\u003c/p\u003e","manuscriptTitle":"Unsatisfactory Response to Acute Medications Does Not Affect the Medication Overuse Headache Development in Pediatric Chronic Migraine","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-03-07 19:53:35","doi":"10.21203/rs.3.rs-4000238/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-03-23T07:06:58+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-03-21T23:03:14+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"7482f1d9-aceb-4287-a8c7-d72828f58d9a","date":"2024-03-10T10:23:32+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-03-10T09:28:16+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-03-05T08:52:21+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-03-05T06:11:13+00:00","index":"","fulltext":""},{"type":"submitted","content":"The Journal of Headache and Pain","date":"2024-02-29T14:41:00+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"the-journal-of-headache-and-pain","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"tjhp","sideBox":"Learn more about [The Journal of Headache and Pain](https://thejournalofheadacheandpain.biomedcentral.com/)","snPcode":"10194","submissionUrl":"https://submission.nature.com/new-submission/10194/3","title":"The Journal of Headache and Pain","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"b6e4cd64-7452-41ec-932e-e2f068e9c5e3","owner":[],"postedDate":"March 7th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-04-23T00:48:16+00:00","versionOfRecord":{"articleIdentity":"rs-4000238","link":"https://doi.org/10.1186/s10194-024-01766-7","journal":{"identity":"the-journal-of-headache-and-pain","isVorOnly":false,"title":"The Journal of Headache and Pain"},"publishedOn":"2024-04-23 00:48:16","publishedOnDateReadable":"April 23rd, 2024"},"versionCreatedAt":"2024-03-07 19:53:35","video":"","vorDoi":"10.1186/s10194-024-01766-7","vorDoiUrl":"https://doi.org/10.1186/s10194-024-01766-7","workflowStages":[]},"version":"v1","identity":"rs-4000238","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4000238","identity":"rs-4000238","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}