Multimodal Physiotherapy Intervention for People With Migraine

2. Scope: Migraine can significantly impair quality of life and pose substantial economicburdens to those affected and society. Migraine, a common neurological disorder thatoften begins in early life, can lead to developmental limitations, high rates of suicide,and reduced work productivity.Migraine could be treated with various physiotherapeutic modalities, especiallyexercises. However, selecting the appropriate treatment approach can be challenging dueto the need for personalized, evidence‐based interventions.At centers like Schmerztherapiezentrum Dr. Brau und Dr. Michel and Capu Motion inOsnabrück, interdisciplinary treatments for migraine are being explored, with a strongemphasis on physiotherapy, which offers a non‐invasive alternative without the sideeffects associated with drugs. While recent advancements in evidence‐based practices havebeen made, their implementation in clinical settings remains scarce.This project aims to optimize physiotherapy interventions by integrating recent evidence,emphasizing a combination of patient education, endurance training, specific exercisesand techniques, and self‐management. By advancing research and applying new evidence inpractice, the project seeks to improve patient outcomes, enhance treatment effectiveness,and reduce healthcare costs, ultimately improving quality of life for individualsaffected by migraine. In addition, this project seeks to understand the interactionsamong biopsychosocial factors, including demographic diversity, physical assessment, andpsychological variables, which are crucial for tailoring interventions. Additionally,considering variations in health systems, treatments, infrastructure, and clinicalpractices, especially within Germany, is essential for developing comprehensive treatmentstrategies for patients suffering from these complex conditions. This research aims toidentify the most effective treatment methods within the German clinical context,potentially serving as a model for other countries and improving global treatmentapproaches for patients with migraine.This pilot trial has several objectives:Primary Objective: To determine whether a three‐month structured multimodal treatmentprogram leads to greater improvement in migraine‐related quality of life compared withusual care, as measured by the Headache Impact Test (HIT‐6™).Secondary Objectives: 1) To compare changes in headache frequency and pain intensitybetween groups; 2) To assess differences in migraine‐related work absenteeism andfunctional impairment; 3) To evaluate adherence to and implementation of the multimodalprogram; 4) In addition, this trial seeks to identify factors (demographic, physical, andpsychosocial) related to treatment success.Since this trial is designed as a pilot feasibility study, our objectives are to estimaterecruitment, retention, and adherence, and to assess the acceptability and feasibility ofimplementing this multimodal treatment in everyday clinical practice.3. Protocol Design: This is a randomized parallel controlled pilot study. This study willcompare a multimodal, evidence‐based intervention consisting of education, relaxationtherapy, guided endurance training, and specific exercises and techniques withconventional physiotherapy. Participants will be randomly assigned to two interventiongroups: group 1: multimodal physiotherapy intervention (MPI) and group 2: standardphysiotherapy.Outcome measures will be recorded at the start of the study (T0) and at the end oftreatment (12 weeks) (T1).In addition, a nested cohort study will be conducted within this RCT to identify factorsassociated with treatment success.Recruitment: Participants will be recruited from the Dr. Brau and Dr. Michel Pain TherapyCentre in Osnabrück, Germany. Potential participants will be informed about the study andinvited to participate by a physician or physiotherapist. In addition, the study will beadvertised on social media platforms and within university settings. Individuals whoexpress interest will be asked to contact the research team, after which a telephoneappointment will be scheduled to provide detailed study information and address anyquestions.Randomization: Participants will be randomly assigned to one of two intervention groupsusing a computer‐generated block randomization procedure, stratified by gender (female,male, diverse) and age group (18‐30, 31‐45, ≥46 years). Randomization will be performedby an independent researcher not otherwise involved in the study.Sample size: for the effectiveness piece, a total of 60 participants (30 per group) willbe recruited. For the primary aim of assessing the feasibility of this study, a samplesize of 60 participants is considered appropriate based on guidelines from pilotprojects. For the prediction piece, a total of 195 patients will be targeted. The samplesize was calculated considering a linear regression model, and the number of potentialindependent variables according to suggested guidelines. When using multiple linearregression, considering a power of 80%, α=0.05, and ten independent variables included inthe model, 155 patients should be included; considering a 20% dropout rate, 195 patientswill be targeted.All patients will be evaluated by a physician, who will make diagnoses and be responsiblefor referring patients to physiotherapy treatment.Interventions: The therapeutic strategies described below will be considered as part ofthe treatment. All participants will have been diagnosed with migraine by a physician atthe pain therapy centre or by an external medical doctor. Most patients receivingtreatment at the centres are likely taking medication prescribed by their physician.Changes to the medication prescribed by the treating physician will be documented duringthe study.The modalities described below will be administered over 18 sessions in line withphysiotherapy standards, making the treatment both realistic and practical forimplementation in a clinical setting. In accordance with the prescribed physiotherapyguidelines, the Schmerztherapiezentrum Dr. Brau und Dr. Michel can issue threeprescriptions with the code 'chronic pain syndrome (CS)' before a six‐month break must betaken. The 18 sessions can be carried out as physiotherapy (Krankengymnastik in Germany)or physiotherapy on equipment (Gerätegestützte Krankengymnastik (KGG)). OneKrankengymnastik (KG) session comprises 20 minutes of individual therapy and can bepassive, active, or educational. One option is to carry them out as a double treatment.This means that two treatments are carried out one after the other. This would then be 40minutes per appointment, with three treatments instead of six per prescription. KGGcomprises 60 minutes with a maximum of three people at a time and involves independenttraining with the support and observation of physiotherapists.Group 1: Multimodal intervention: the multimodal physiotherapy treatment will bedelivered by trained physiotherapists. The treatment has different components asdescribed below: 1. Education: The subjects will receive a presentation on migraine pain via YouTubevideo. They are encouraged to watch it before starting physiotherapy. They can thenask questions during therapy. The presentation, spanning approximately 80 minutes,introduces a patient from the physiotherapist's practice to discuss migraine, aswell as the associated treatment. The patient's symptoms and treatment journey areused to provide both theoretical and practical insights about their condition.During the presentation, the patient is repeatedly referenced to convey the topicnot only theoretically but also practically. This is because migraine is awidespread condition. 2. Aerobic exercise: Patients are encouraged to regularly engage in endurance sports ontheir own. Endurance sports are a form of training characterised by 'repeated,structured physical activity in which the body's metabolism requires oxygen toproduce energy. Large muscle groups are repeatedly exercised, and the heart rate iskept elevated for a longer period of time (between 20 and 60 minutes). Examplesinclude cycling, running, hiking, swimming and walking. Patients will be instructedto use their heart rate and the Borg scale to target the training. High‐IntensityInterval Training (HIIT) will be targeted per literature endorsements and positiveeffects. The training will depend on each subject's own assessment and preferences. 3. Relaxation therapy: In addition, participants are encouraged to practise relaxationtechniques daily, as these have been shown to have positive results in some studies.Relaxation therapy appears to reduce the frequency and intensity of migraineattacks, alleviate chronic pain symptoms (including neck pain), decrease the needfor medication, and improve psychological parameters such as self‐efficacy, anxiety,and depression. This is due to stress reduction and positive effects on theautonomic nervous system. Patients are shown a video on YouTube about the breathingtechnique 4‐7‐8, that they are asked to follow.The 4‐7‐8 breathing technique has a relaxing effect, relieves stress, and helpspeople to calm down. The name already reveals how it works: the patient is asked tobreathe in for 4 seconds, hold the breath for 7 seconds, and then breathe out for 8seconds. Then this is repeated at least 8 times. The exercise can be performed insitting, standing, or lying down. 4. Specific exercises and physiotherapy techniques: The following plan for specificexercises and techniques of the multimodal treatment is suggested: 1. Session 1+ 2 (40 minutes): Detailed findings with a physical and objective examination of the structures that induce and influence headaches, the physical examination will be conducted according to the physiotherapist training and reasoning to deliver the manual therapy and exercise programs (e.g., passive physiological intervertebral movements, additional movements of the upper cervical spine, examination of myofascial trigger points in the head and neck area, among others). 2. Session 3+4 (40 minutes): Repetition and discussion of pain education and the home exercise programme, passive techniques: Manual techniques (especially passive physiological intervertebral movements (PPIVMs) C1‐C3), soft tissue techniques of the affected structures (trigger point therapy of the painful muscle), instructions for self‐massage of the painful muscles 3. Session 5+6 (40 minutes): Revision of therapy: Revision of manual techniques, soft tissue techniques, and self‐massage, learning how to activate the deep neck flexors and extensors, strengthening the shoulder girdle muscles, answering individual questions 4. Session 7 (60 minutes with a maximum of 3 participants): At least 30 minutes on an ergometer with a heart rate monitor and training at the appropriate heart rate. 5. Sessions 8‐12 (60 minutes with a maximum of 3 participants): Independent training: Activation of deep neck flexors and extensors, strengthening of the shoulder girdle muscles, exercises for the jaw, stretching and self‐massage of hypertonic muscles, exercises for balance and the vestibular system.Compliance Adherence to the on‐site session will be recorded by the therapist. Compliancewith the home exercise program will be monitored via Research Electronic Data Capture(REDCap). Participants will be prompted to record their daily activity in a diary,documenting exactly how often and consistently they perform the prescribed exercises.Co‐interventions Participants will be asked to refrain from undergoing new treatmentsduring the study to avoid co‐interventions. Any changes to the trial protocol will berecorded in REDCap by the researchers and accounted for in the final analyses.Patients will be assessed regarding outcomes (see outcomes section) and baselineinformation. The following baseline information will be collected in addition to theoutcomes 1. Patient characteristics (e.g., age, sex, pain characteristics, treatment history). 2. Comorbidities: Subjects will be requested to draw on a body map any additional painlocations, as well as any additional diagnosed conditions. 3. Diagnostic criteria for Temporomandibular disorders: A complete examination of thecraniomandibular system using the Diagnostic Criteria for TemporomandibularDisorders (DC/TMD) will be used.It is important to highlight that the psychometric properties of the outcomes used inthis study have been extensively supported in the literature to be used in patients withmigraine. These variables will be collected at the baseline and at the end of thetreatment period, with the exception of the patients' characteristics and DC/TMDquestionnaire and physical assessment, which will be collected only at the baseline. Inaddition, questionnaires on self‐perceived improvement and the therapeutic alliance willbe collected only at the end of treatment.Feasibility outcomes Additionally, this study will focus on the feasibility and clinicalapplicability of the intervention. Three criteria to determine the success of a trialhave been established: 1) recruitment rate: at least 30‐40% of eligible subjects arerecruited and randomized; 2) retention: drop out during the intervention period cannotexceed 33%; 3) adherence: At least 66% of participants tolerate the intervention and ≥70%adhere to the protocol. Based on these recommendations and the feedback from patients andtherapists, the investigators will modify our protocol to maximize feasibility in asubsequent trial. This will be assessed using a questionnaire completed by the patientsand physiotherapists in the intervention group. The questionnaire will explore keyaspects of implementing the intervention in routine clinical practice.Analyses Feasibility outcomes (i.e., recruitment rate, retention, adherence) will bedescriptively analyzed.The descriptive parameters, such as the mean and standard deviation, will be used todescribe the characteristics of the sample, such as demographic and clinicalcharacteristics, and changes within the groups. Of interest are frequency distributionsfor categorical variables (e.g., gender, type of treatment, and migraine frequency, andneck pain history among others). Subsequently, inferential statistical tests are used toexamine the differences between the intervention and comparison groups.The analysis of effectiveness will follow the intention‐to‐treat principles. Efficacyanalysis will follow the per‐protocol (compliers only; >70% of intervention) andas‐treated (intervention received) principles. Due to the pilot design of the study andthe small sample size used, statistical analyses will be exploratory, and effect sizeswill be calculated to enlighten the clinical significance of these findings. Theinvestigators will use Cohen's d with pooled standard deviation to display the effectsizes. To calculate Cohen's d, the Cambridge effect size calculator Excel tool will beused (https://www.cem.org/effect‐size‐calculator) complemented with RevMan 5.4calculations to display forest plots To investigate the objectives of this study, twoanalyses will be performed. The analyses include 1) within‐group and 2) between‐groupdifferences.Paired t‐test will be conducted to test the within‐group differences, and theWilcoxon‐Rank Test to confirm p‐values. For testing differences between two independentgroups (between‐groups difference), one‐way ANOVA with Welch's t‐test adjustment will beconducted. Two necessary assumptions for conducting ANOVA are normally distributed dataas well as the homogeneity of variances for both groups. ANOVA test and t‐tests are veryrobust to violations of normality when the sample sizes between groups are similar.However, the results of these tests can be affected by violations of homogeneity ofvariance. According to Rasch et al., pre‐testing leads to an unknown risk of type‐I andtype‐II errors, so they recommended the Welch's t‐test without pre‐testing over otherstatistical tests. This is supported by Ruxton et al., recommending the use of Welch'st‐test over other statistical tests, e.g. the Mann‐Whitney‐U‐Test.The primary analysis will be conducted using linear mixed‐effects models to evaluate theeffectiveness of the intervention on migraine‐related disability as measured by theHeadache Impact Test (HIT‐6™). Given the longitudinal structure of the data, withrepeated measurements (e.g., baseline and post‐intervention) nested within individuals, amultilevel modeling approach will be applied to account for within‐subject correlations.Fixed effects will include treatment group (multimodal intervention vs usual care), time,and the group × time interaction, which represents the primary effect of interest.Additional covariates of interest, such as baseline pain intensity and treatmentexpectancy, will be included as fixed effects to explore their influence on treatmentoutcomes. A random intercept for participants will be included to account for individualvariability. If appropriate, additional random effects (e.g., therapist or treatmentsite) will be considered. Linear mixed‐effects models are robust to missing data underthe assumption of missing at random (MAR). If necessary, sensitivity analyses usingmultiple imputations will be conducted to assess the impact of missing data on theresults.To identify factors related to treatment success of different exercise modalities, theinvestigators will perform two different analyses: 1) considering headache disability(Headache Impact Test Short Form (HIT‐6TM)) (continuous variable) (continuous variable)as an outcome, and 2) using the response to treatment as an outcome using the GRS(dichotomous outcome). Participants will be classified as responders and non‐respondersaccording to the 15‐point GRS for each treatment group at the end of the treatment. Toclassify patients as responders and non‐responders, a cut‐off value of ±4 points ofchange (for improvement or worsening) will be chosen; this would assure a moderatechange. The main time point will be the end of the treatment. Both models will be builtbased on the following procedures: 1) univariate single linear/logistic regressionanalysis will be performed to determine the association between the independent variables(possible predictor factors) and the dependent variables of interest (headache disability(Headache Impact Test Short Form (HIT‐6TM)), GRS). The independent variables that aresignificant with a p≤0.2 will be considered in the first multivariate linear/logisticregression model. Models will be constructed with and without the inclusion of baselineheadache frequency to explore its contribution. The investigators then proceed to abackward elimination process to select the most significant variables. Variables will beentered into or hierarchically removed from the multivariate model, based on the AkaikeInformation Criterion. As a second option, the Least Absolute Shrinkage and SelectionOperator (LASSO) algorithm will be applied to automatically select the relevantcharacteristics and regularize the model. The selection of variables for the multivariatemodel will be based on both the level of significance and the magnitude of thecoefficients obtained through LASSO. This type of analysis is used in data with a largenumber of variables and small sample sizes, thus avoiding overfitting and selecting thebest predictive model. Once the ideal model has been selected, a nomogram will be createdand validated to provide an intuitive visual tool for predicting treatment response basedon the analyses. The receiver‐operating characteristic (ROC) curve will be used to assesseach variable's ability to discriminate between responders and non‐responders, followingestablished guidelines (logistic regression).Research team Principal investigator: Prof. Dr. Susan Armijo‐OlivoOther scientists who will conduct the research:Marie Marks (B.Sc. M.Sc. cand.) Dr. Ester Castro‐Carletti, PhD MSc. PT Cristian JustriboManion MSc. PT Sabiha Irem Sancaktar Short‐term students from Bachelor's, Master's, andPh.D.