Does pain self-efficacy predict, moderate or mediate outcomes in people with chronic headache; an exploratory analysis of the CHESS trial.

BACKGROUND: Chronic headache disorders are disabling. The CHESS trial studied the effects of a short non-pharmacological intervention of education with self-management support for people affected by migraine and/or tension type headache for at least 15 days per month for at least three months. There were no statistically significant effects on the Headache Impact Test-6 (HIT-6) at 12-months. However, we observed improvement in pain self-efficacy questionnaire (PSEQ) and short-term HIT-6. We explored the impact of the CHESS intervention on PSEQ, and subsequently, on the HIT-6 and chronic headache quality of life questionnaire (CH-QLQ) at four, eighth and 12 months. METHODS: We included all 736 participants from the CHESS trial. We used simple linear regression models to explore the change of HIT-6 and CH-QLQ with treatment and PSEQ at baseline (predictor analysis), and the interaction between treatment and baseline PSEQ (moderator analysis). We considered the change of PSEQ from baseline to four months as a mediator in the mediation analysis. RESULTS: Baseline PSEQ neither predicted nor moderated outcomes. The prediction effect on change of HIT-6 from baseline to 12 months was 0.01 (95% CI, -0.03 to 0.04) and the interaction (moderation) effect was -0.07 (95% CI, -0.15 to 0.002). However, the change of PSEQ from baseline to 4-month mediated the HIT-6 (baseline to 8-, and 12-month) and all components of CH-QLQ (baseline to 8-, and 12-month). The CHESS intervention improved the mediated variable, PSEQ, by 2.34 (95% CI, 0.484 to 4.187) units and this corresponds to an increase of 0.21 (95% CI, 0.03 to 0.45) units in HIT-6 at 12-months. The largest mediated effect was observed on the CH-QLQ Emotional Function, an increase of 1.12 (95% CI, 0.22 to 2.20). CONCLUSIONS: PSEQ was not an effective predictor of outcome. However, change of short-term PSEQ mediated all outcomes, albeit minimally. Future behavioural therapy for chronic headache may need to consider how to achieve larger, and more sustained increases level of self-efficacy than that achieved within the CHESS trial. TRIAL REGISTRATION: ISRCTN79708100.

Characterizing gaps in the preventive pharmacologic treatment of migraine: Multi-country results from the CaMEO-I study.

OBJECTIVE: To analyze data from the Chronic Migraine Epidemiology and Outcomes-International (CaMEO-I) Study in order to characterize preventive medication use and identify preventive usage gaps among people with migraine across multiple countries. BACKGROUND: Guidelines for the preventive treatment of migraine are available from scientific organizations in various countries. Although these guidelines differ among countries, eligibility for preventive treatment is generally based on monthly headache day (MHD) frequency and associated disability. The overwhelming majority of people with migraine who are eligible for preventive treatment do not receive it. METHODS: The CaMEO-I Study was a cross-sectional, observational, web-based panel survey study performed in six countries: Canada, France, Germany, Japan, the United Kingdom, and the United States. People were invited to complete an online survey in their national language(s) to identify those with migraine according to modified International Classification of Headache Disorders, 3rd edition, criteria. People classified with migraine answered questions about current and ever use of both acute and preventive treatments for migraine. Available preventive medications for migraine differed by country. MHD frequency and associated disability data were collected. The American Headache Society (AHS) 2021 Consensus Statement algorithm was used to determine candidacy for preventive treatment (i.e., ≥3 monthly MHDs with severe disability, ≥4 MHDs with some disability, or ≥6 MHDs regardless of level of disability). RESULTS: Among 90,613 valid completers of the screening survey, 14,492 met criteria for migraine and completed the full survey, with approximately 2400 respondents from each country. Based on the AHS consensus statement preventive treatment candidacy algorithm, averaging across countries, 36.2% (5246/14,492) of respondents with migraine qualified for preventive treatment. Most respondents (84.5% [4431/5246]) who met criteria for preventive treatment according to the AHS consensus statement were not using a preventive medication at the time of the survey. Moreover, 19.3% (2799/14,492) of respondents had ever used preventive medication (ever users); 58.1% (1625/2799) of respondents who reported ever using a preventive medication for migraine were still taking it. Of the respondents who were currently using a preventive medication, 50.2% (815/1625) still met the criteria for needing preventive treatment based on the AHS consensus statement. CONCLUSIONS: Most people with migraine who qualify for preventive treatment are not currently taking it. Additionally, many people currently taking preventive pharmacologic treatment still meet the algorithm criteria for needing preventive treatment, suggesting inadequate benefit from their current regimen.

Consensus recommendations on the role of nurses in headache care: A European e-Delphi study.

BACKGROUND: Nurses work at headache centres throughout Europe, and their care for migraine patients is acknowledged. However, the specific roles and tasks of nursing vary, and a unified understanding is lacking, posing challenges to knowledge sharing and research. OBJECTIVES: Using an e-Delphi study method, the objective is to obtain healthcare professional headache experts' opinions on nursing-specific roles and tasks and combine this into consensus statements for nurse recommendations for migraine treatment. METHODS: A three-round questionnaire study was conducted with nurses and neurologists from 18 specialised headache centres in 10 countries. In round 1, statements were compiled from a systematic examination of existing literature and expert opinions. In rounds 2 and 3, the experts rated the importance of statements (from round 1) on a 5-point Likert scale. Statements were analysed using a content analysis method, and the consensus of pre-defined statements was evaluated with gradually increased predetermined criteria using descriptive statistics. RESULTS: Twenty-one experts, representing all 10 countries, participated. The predetermined consensus of ≥70% agreement was reached for 42 out of the initial 63 statements. These statements formed the final recommendations within two themes: "The nurses' roles and tasks in the clinical setting" and "The nurses' roles and tasks in educating patients and colleagues." The consensus level of statements was strong, with 40% receiving unanimous agreement (100%) and 97% achieving relatively high agreement (>80%). CONCLUSION: Nursing plays a vital role with diverse tasks in migraine care. This study offers practical recommendations and a framework for nurses, equipping them with a clinical tool to enhance care and promote a coordinated approach to migraine treatment.

What predicts citation counts and translational impact in headache research? A machine learning analysis.

BACKGROUND: We aimed to develop the first machine learning models to predict citation counts and the translational impact, defined as inclusion in guidelines or policy documents, of headache research, and assess which factors are most predictive. METHODS: Bibliometric data and the titles, abstracts, and keywords from 8600 publications in three headache-oriented journals from their inception to 31 December 2017 were used. A series of machine learning models were implemented to predict three classes of 5-year citation count intervals (0-5, 6-14 and, >14 citations); and the translational impact of a publication. Models were evaluated out-of-sample with area under the receiver operating characteristics curve (AUC). RESULTS: The top performing gradient boosting model predicted correct citation count class with an out-of-sample AUC of 0.81. Bibliometric data such as page count, number of references, first and last author citation counts and h-index were among the most important predictors. Prediction of translational impact worked optimally when including both bibliometric data and information from the title, abstract and keywords, reaching an out-of-sample AUC of 0.71 for the top performing random forest model. CONCLUSION: Citation counts are best predicted by bibliometric data, while models incorporating both bibliometric data and publication content identifies the translational impact of headache research.

Adverse and serious adverse events incidence of pharmacological interventions for managing chronic and episodic migraine in adults: a systematic review.

Background: Migraine is the second most common prevalent disorder worldwide and is a top cause of disability with a substantial economic burden. Many preventive migraine medications have notable side effects that affect different body organs. Method: We systematically searched for published randomised controlled trials (RCTs) using terms for migraine/headache and preventive medications. Using eligibility criteria, two reviewers independently assessed the articles. Cochrane risk-of-bias tool was applied to assess the quality of the studies. Data were classified by system organ class (SOC). Results: Thirty-two RCTs with 21 780 participants met the eligibility criteria for the incidence of adverse events (AEs). Additionally, 33 RCTs with 22 615 participants were included to synthesise the incidence of serious AEs (SAEs). The percentage of attributed AEs and SAEs to each SOC for 10 preventive drugs with different dosing regimens was calculated. Amitriptyline and topiramate had a higher incidence of nervous system disorders; Topiramate was also associated with a higher incidence of psychiatric disorders. All drugs showed a certain incidence of infections and infestations, with Onabotulinumtoxin A (BTA) having the lowest rate. BTA had a higher incidence of musculoskeletal disorders than the other drugs. Calcitonin gene-related peptide (CGRP) monoclonal antibodies (MAbs) such as fremanezumab and galcanezumab were linked to more general disorders and administration site conditions than other drugs. Conclusion: Notably, the observed harm to SOCs varies among these preventive drugs. We suggest conducting head-to-head RCTs to evaluate the safety profile of oral medications, BTA, and CGRP MAbs in episodic and/or chronic migraine populations. PROSPERO registration number: CRD42021265993.

Cognitive assessment during the phases of a spontaneous migraine: a prospective cohort study.

INTRODUCTION: Cognitive symptoms are reported commonly throughout all phases of a migraine; however, there is a paucity of objective cognitive profiling. Previous studies have been limited by practice effect, and variable populations. METHODS: Participants completed 1 month of daily testing with a computerised cognitive battery involving a simple reaction (SRT), choice reaction (CRT) and a working memory test (WM). Results were correlated with their diary to identify interictal scores, and scores during each phase of a migraine, and non-migraine headache days. RESULTS: A total of 16 patients with episodic migraine participated. During the headache phase of a migraine, responses to SRT, CRT and WM tasks were significantly slower and less accurate than interictally. During the postdrome, WM task performance was slower and less accurate. Non-migraine headache days were not associated with significant change. CONCLUSION: The headache and postdromal phase of a migraine day was associated with objective evidence of cognitive dysfunction in patients with episodic migraine.

Relationship of migraine and other forms of chronic pain.

The disability of migraine, a highly prevalent condition, is worsened by a second comorbid chronic pain condition. There is evidence of a relationship between migraine and several visceral pain conditions including irritable bowel syndrome, endometriosis, and dysmenorrhoea, as well as nonvisceral conditions including temporomandibular dysfunction, fibromyalgia, and lower back pain. While the mechanisms linking these conditions are inadequately surmised, a two-way relationship between migraine and these comorbidities likely exists. The progression and chronification of migraine is associated with peripheral and central sensitization, which may predispose to other conditions. Conversely, aspects of the mechanism of each comorbid condition may promote further migraine attacks. This chapter introduces each comorbidity, briefly summarizes the existing evidence, and discusses implications for treatment.

Twelve-month efficacy of CGRP monoclonal antibodies and predictive value of short-term response: results of an Australian multicentre study.

Introduction: Clinical trials show that calcitonin gene-related peptide monoclonal antibodies (CGRP mAbs) are effective preventative treatments for chronic migraine. Their efficacy over longer time periods and in cohorts originally excluded from trials remains uncertain. This study aims to explore the impact of CGRP mAbs in an Australian real-life setting. Methods: A multicentre cohort study was performed in the tertiary headache clinics of the Alfred and Austin Hospitals, Melbourne, Australia. Patients were commenced on a CGRP mAb for chronic migraine and asked to keep a headache diary, recorded at 3 monthly appointments for 12 months. Primary outcome was a ≥50% reduction in monthly headache days (MHD). Results: From a population of 105 patients, 90 patients commenced galcanezumab and 15 commenced fremanezumab. The ≥50% responder rate of the cohort was 52.4% after 3 months. Over 12 months follow-up, 25.7% of the cohort ceased due to a lack of efficacy and 16.2% ceased due to an adverse event. There was no difference in response or cessation between medications. There was poor agreement in 3-month and 12-month response rates (Cohen's κ=0.130; p=0.171). On subgroup analysis, continuous headache at baseline and number of trialled preventative treatments were the only factors associated with efficacy. Conclusion: CGRP mAbs were associated with sustained reductions in MHD over 12-month follow-up in patients with resistant migraine in Australia. Further studies are required to determine treatment options for patients with continuous headache. Poor agreement between outcomes at 3 and 12 months highlights the need to assess some patients at later timepoints.

Spontaneous intracranial hypotension.

Spontaneous intracranial hypotension (SIH) is a highly disabling but treatable secondary cause of headache. Recent progress in neuroradiological techniques has catalysed understanding of its pathophysiological basis and clinical diagnosis, and facilitated the development of more effective investigation and treatment methods. A UK-based specialist interest group recently produced the first multidisciplinary consensus guideline for the diagnosis and treatment of SIH. Here, we summarise a practical approach to its clinical and radiological diagnosis, symptomatic and non-targeted interventional treatment, radiological identification of leak site and targeted treatment of the leak once it has been localised.

Clinical effectiveness of pharmacological interventions for managing chronic migraine in adults: a systematic review and network meta-analysis.

BACKGROUND: Chronic migraine can be a profoundly disabling disorder that may be treated with preventive medications. However, uncertainty remains as to which preventive medication is the most effective. We present a network meta-analysis to determine the effectiveness and rank of preventive drugs for chronic migraine in adults. METHODS: We identified, reviewed, and extracted data from randomised controlled trials (RCTs) of preventive drugs for chronic migraine with at least 200 participants. Data were analysed using network meta-analysis. FINDINGS: We included 12 RCTs of six medications (Eptinezumab, Erenumab, Fremanezumab, Galcanezumab, Onabotulinumtoxin A, and Topiramate) compared to placebo or each other. All drugs effectively reduced monthly headache and migraine days compared with placebo. The most effective drug for monthly headache days was Eptinezumab 300mg, with a mean difference of -2.46 days, 95% Credible Interval (CrI): -3.23 to -1.69. On the Surface Under the Cumulative Ranking Area (SUCRA) analysis, the probability that Eptinezumab 300mg was ranked highest was 0.82. For monthly migraine days, the most effective medication was Fremanezumab-monthly, with a mean difference: -2.77 days, 95% CrI: -3.36 to -2.17, and 0.98 probability of being ranked the highest. All included drugs, except Topiramate, improved headache-related quality of life. No eligible studies were identified for the other common preventive oral medications such as Amitriptyline, Candesartan, and Propranolol. The main reasons were that the studies did not define chronic migraine, were undertaken before the definition of chronic migraine, or were too small. INTERPRETATION: All six medications were more effective than the placebo on monthly headache and migraine days. The absolute differences in the number of headache/migraine days are, at best, modest. No evidence was found to determine the relative effectiveness of the six included drugs with other oral preventive medications. REGISTRATION: PROSPERO (number CRD42021265990).

Competing treatments for migraine: a headache for decision-makers.

BACKGROUND: Migraine is the world's second most common disabling disorder, affecting 15% of UK adults and costing the UK over £1.5 billion per year. Several costly new drugs have been approved by National Institute for Health and Care Excellence. AIM: To assess the cost-effectiveness of drugs used to treat adults with chronic migraine. METHODS: We did a systematic review of placebo-controlled trials of preventive drugs for chronic migraine. We then assessed the cost-effectiveness of the currently prescribable drugs included in the review: Onabotulinum toxin A (BTA), Eptinezumab (100mg or 300mg), Fremanezumab (monthly or quarterly dose), Galcanezumab or Topiramate, each compared to placebo, and we evaluated them jointly. We developed a Markov (state-transition) model with a three-month cycle length to estimate the costs and quality-adjusted life years (QALYs) for the different medications from a UK NHS and Personal Social Services perspective. We used a two-year time horizon with a starting age of 30 years for the patient cohort. We estimated transition probabilities based on monthly headache days using a network meta-analysis (NMA) developed by us, and from published literature. We obtained costs from published sources and applied discount rates of 3.5% to both costs and outcomes. RESULTS: Deterministic results suggest Topiramate was the least costly option and generated slightly more QALYs than the placebo, whereas Eptinezumab 300mg was the more costly option and generated the most QALYs. After excluding dominated options, the incremental cost-effectiveness ratio (ICER) between BTA and Topiramate was £68,000 per QALY gained and the ICER between Eptinezumab 300mg and BTA was not within plausible cost-effectiveness thresholds. The cost-effectiveness acceptability frontier showed that Topiramate is the most cost-effective medication for any amount the decision maker is willing-to-pay per QALY. CONCLUSIONS: Among the various prophylactic medications for managing chronic migraine, only Topiramate was within typical cost-effectiveness threshold ranges. Further research is needed, ideally an economic evaluation alongside a randomised trial, to compare these newer, expensive CGRP MAbs with the cheaper oral medications.

Abdominal migraine and cyclical vomiting syndrome.

Abdominal migraine and cyclical vomiting syndrome (CVS) are characteristic syndromes which have overlapping characteristics with migraine but lack the cardinal symptom of headache. Both abdominal migraine and CVS are characterized by recurrent attacks of nausea, vomiting, and/or abdominal pain lasting hours to a few days, with symptom freedom between attacks. Both abdominal migraine and CVS typically occur in children and adolescents, who often go on to develop more typical migraine headaches when older, but may also present for the first time in adults. Due to their shared characteristics and association with migraine headaches, abdominal migraine and CVS are sometimes called "migraine equivalents," and their pathophysiology is assumed to overlap with migraine headache. This chapter describes what is known about the clinical characteristics, epidemiology, pathophysiology, and prognosis of abdominal migraine and CVS, and explores their relationship to migraine. We also review the existing evidence for the nonpharmacological management, acute treatment of attacks, and preventive treatments for both abdominal migraine and CVS.

Epidemiology of migraine.

Migraine affects over a billion people worldwide and brings with it a huge burden of disability. It is a disease which disproportionally affects the working age population which heightens its economic impact, both at the individual family level and the societal level. Women are significantly more affected by migraine at every age and in all social and geographical groups. At the most severe end of the spectrum, chronic migraine is associated with poorer overall physical and mental health as well as increased risk of unemployment and lower household income. Estimates of the incidence and prevalence of migraine vary with sex, race, ethnicity, geography, socioeconomic, and educational status, suggesting there are many factors at play. In many cases, it is not clear whether these factors are causative of migraine, the effects of migraine, or (as is most likely) a combination of both. Future studies should aim to clarify these links, so that modifiable factors can be addressed where possible and those at risk of developing chronic migraine might receive targeted treatment at an early stage.

Association of Clinical and Neuroanatomic Factors With Response to Ventral Tegmental Area DBS in Chronic Cluster Headache.

BACKGROUND AND OBJECTIVES: Deep brain stimulation (DBS) of the ventral tegmental area (VTA) is a surgical treatment option for selected patients with refractory chronic cluster headache (CCH). We aimed to identify clinical and structural neuroimaging factors associated with response to VTA DBS in CCH. METHODS: This prospective observational cohort study examines consecutive patients with refractory CCH treated with VTA DBS by a multidisciplinary team in a single tertiary neuroscience center as part of usual care. Headache diaries and validated questionnaires were completed at baseline and regular follow-up intervals. All patients underwent T1-weighted structural MRI before surgery. We compared clinical features using multivariable logistic regression and neuroanatomic differences using voxel-based morphometry (VBM) between responders and nonresponders. RESULTS: Over a 10-year period, 43 patients (mean age 53 years, SD 11.9), including 29 male patients, with a mean duration of CCH 12 years (SD 7.4), were treated and followed up for at least 1 year (mean follow-up duration 5.6 years). Overall, there was a statistically significant improvement in median attack frequency from 140 to 56 per month (Z = -4.95, p < 0.001), attack severity from 10/10 to 8/10 (Z = -4.83, p < 0.001), and duration from 110 to 60 minutes (Z = -3.48, p < 0.001). Twenty-nine (67.4%) patients experienced ≥50% improvement in attack frequency and were therefore classed as responders. There were no serious adverse events. The most common side effects were discomfort or pain around the battery site (7 patients) and transient diplopia and/or oscillopsia (6 patients). There were no differences in demographics, headache characteristics, or comorbidities between responders and nonresponders. VBM identified increased neural density in nonresponders in several brain regions, including the orbitofrontal cortex, anterior cingulate cortex, anterior insula, and amygdala, which were statistically significant (p < 0.001). DISCUSSION: VTA DBS showed no serious adverse events, and, although there was no placebo control, was effective in approximately two-thirds of patients at long-term follow-up. This study did not reveal any reliable clinical predictors of response. However, nonresponders had increased neural density in brain regions linked to processing of pain and autonomic function, both of which are prominent in the pathophysiology of CCH.

Phenotype of new daily persistent headache: subtypes and comparison to transformed chronic daily headache.

BACKGROUND: It is unknown whether new daily persistent headache (NDPH) is a single disorder or heterogenous group of disorders, and whether it is a unique disorder from chronic migraine and chronic tension-type headache. We describe a large group of patients with primary NDPH, compare its phenotype to transformed chronic daily headache (T-CDH), and use cluster analysis to reveal potential sub-phenotypes in the NDPH group. METHODS: We performed a case-control study using prospectively collected clinical data in patients with primary NDPH and T-CDH (encompassing chronic migraine and chronic tension-type headache). We used logistic regression with propensity score matching to compare demographics, phenotype, comorbidities, and treatment responses between NDPH and T-CDH. We used K-means cluster analysis with Gower distance to identify sub-clusters in the NDPH group based on a combination of demographics, phenotype, and comorbidities. RESULTS: We identified 366 patients with NDPH and 696 with T-CDH who met inclusion criteria. Patients with NDPH were less likely to be female (62.6% vs. 73.3%, p < 0.001). Nausea, vomiting, photophobia, phonophobia, motion sensitivity, vertigo, and cranial autonomic symptoms were all significantly less frequent in NDPH than T-CDH (p value for all < 0.001). Acute treatments appeared less effective in NDPH than T-CDH, and medication overuse was less common (16% vs. 42%, p < 0.001). Response to most classes of oral preventive treatments was poor in both groups. The most effective treatment in NDPH was doselupin in 45.7% patients (95% CI 34.8-56.5%). Cluster analysis identified three subgroups of NDPH. Cluster 1 was older, had a high proportion of male patients, and less severe headaches. Cluster 2 was predominantly female, had severe headaches, and few associated symptoms. Cluster 3 was predominantly female with a high prevalence of migrainous symptoms and headache triggers. CONCLUSIONS: Whilst there is overlap in the phenotype of NDPH and T-CDH, the differences in migrainous, cranial autonomic symptoms, and vulnerability to medication overuse suggest that they are not the same disorder. NDPH may be fractionated into three sub-phenotypes, which require further investigation.

The short-term effects of CGRP monoclonal antibodies on bone turnover: A prospective cohort study.

BACKGROUND: Calcitonin gene-related peptide monoclonal antibodies (CGRP mAb) are an effective treatment of migraine however may have possible off-target effects. Pre-clinical studies implicate CGRP in several aspects of bone turnover and homeostasis. The clinical effect of CGRP mAb on bone turnover is not known, however. METHODS: Between June 2021 and July 2022, a multi-centre prospective cohort study was undertaken with eligible patients undergoing paired testing of the validated bone turnover markers procollagen type I N-terminal propeptide (P1NP) and serum C-terminal telopeptide of type I collagen (CTX) prior to and at least three months following administration of a CGRP mAb. RESULTS: A total of 45 patients with a mean age of 41.8 (SD 11.9) were included in the final analysis, all of whom received a ligand-targeting CGRP mAb. Administration of a CGRP mAb was associated with a statistically significant increase in P1NP from 44.5 microg/L to 51.5 microg/L (p = 0.004), but no significant change in CTX. CONCLUSION: In otherwise homeostatic conditions, short-term administration of a CGRP mAb is associated with increased P1NP, a bone formation marker but not with increased CTX, a bone resorption marker. Further study is required to validate these findings over longer time periods, in a larger cohort, and in pre-existing states of increased calcium stress and bone-turnover.

Chronic Migraine Epidemiology and Outcomes - International (CaMEO-I) Study: Methods and multi-country baseline findings for diagnosis rates and care.

BACKGROUND: The Chronic Migraine Epidemiology and Outcomes-International study provides insight into people with migraine in multiple countries. METHODS: This cross-sectional, observational, web-based cohort study was conducted in Canada, France, Germany, Japan, United Kingdom, and United States. An initial Screening Module survey solicited general healthcare information from a representative sample and identified participants with migraine based on modified International Classification of Headache Disorders-3 criteria; those with migraine completed a detailed survey based on validated migraine-specific assessments. RESULTS: Among 90,613 people who correctly completed the screening surveys, 76,121 respondents did not meet the criteria for migraine, while 14,492 did. Among respondents with migraine, mean age ranged from 40 to 42 years. The median number of monthly headache days ranged from 2.33 to 3.33 across countries, while the proportion of respondents with moderate-to-severe disability (measured by Migraine Disability Assessment) ranged from 30% (Japan) to 52% (Germany). The proportion of respondents with ≥15 monthly headache days ranged from 5.4% (France) to 9.5% (Japan). Fewer than half of respondents with migraine in each country reported having received a migraine diagnosis. CONCLUSION: These results demonstrated high rates of migraine-related disability and underdiagnosis of migraine across six countries. This study will characterize country-level burden, treatment patterns, and geographical differences in care.