https://orcid.org/0000-0002-4340-0069
Figures
Abstract
Introduction
Botulinum toxin injections are a common treatment for managing spasticity resulting from central nervous system damage, including stroke, multiple sclerosis, and traumatic brain injury. However, the injections are associated with perceived pain, and many patients experience significant anticipatory stress regarding future sessions. The intensity of this stress varies among individuals. Music therapy, particularly receptive musical interventions structured around a U-shaped sequence, promotes progressive relaxation through distinct musical phases. This method has demonstrated efficacy in reducing pain and anxiety across various clinical contexts, including chronic and acute pain, Alzheimer’s disease, fibromyalgia, and neurologically mediated pain. Given the painful nature of botulinum toxin injections, this study proposes the use of receptive music therapy to improve patient tolerance of the procedure. We hypothesize that receptive musical intervention can reduce injection-induced stress in adults undergoing botulinum toxin treatment. To our knowledge, no studies have specifically investigated the effect of music therapy on stress related to botulinum toxin injections. We aim to conduct a prospective randomized (1:1) controlled trial to evaluate the impact of receptive music intervention on stress levels, measured via heart rate variability (HRV), during botulinum toxin injection sessions. The primary objective is to assess the effect of receptive musical intervention during botulinum toxin injections on injection-induced stress, measured by HRV. Secondary objectives include evaluating the intervention’s effects on pain intensity and anxiety levels.
Methods and analysis
Patient satisfaction following the music-assisted injection session will also be assessed. Additionally, the physician’s evaluation of the procedure and the patient’s perception of time during the session will be recorded.
Ethics and dissemination
All participants will provide written informed consent prior to enrollment. The study has received approval from the relevant institutional ethics committee (Comité de Protection des Personnes – ID: 25.00156.000468, Sud-Méditerranée IV, approved on 3 April 2025). Findings will be disseminated through peer-reviewed publications and presentations at scientific conferences.
Citation: Angelvy P, Badin M, Pelletier-Visa M, Givron P, Pereira B, Coudeyre E (2025) Musical intervention to reduce stress during botulinum toxin injection for spasticity: Protocol for a randomized controlled trial (MUSIBOT). PLoS One 20(11): e0327259. https://doi.org/10.1371/journal.pone.0327259
Editor: Maheshkumar Baladaniya, Neighborhood Physical Therapy, UNITED STATES OF AMERICA
Received: July 7, 2025; Accepted: October 12, 2025; Published: November 25, 2025
Copyright: © 2025 Angelvy et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: This article is a research protocol and does not present any scientific results.
Funding: The author(s) received no specific funding for this work.
Competing interests: The authors have declared that no competing interests exist.
Introduction
Botulinum toxin (BT) injections are an effective treatment for spasticity caused by central neurological system lesions [1] and are widely used in people with conditions such as stroke, multiple sclerosis, spinal cord injury and traumatic brain injury. Botulinum toxin has been a reference treatment for focal spasticity since the recommendations of the SOFMER of 2009 [2]. However, as the effect of the botulinum toxin lasts approximately 3 months, the injections must be repeated several times per year. These injections are often perceived as painful. As well as the skin break in and the injection of the product, the technique used to guide the injections may cause pain, particularly electrical stimulation. Some injection sites are more painful than others, such as the palms of the hands and soles of the feet [3]. Injection tolerance varies across individuals, but most experience significant levels of stress during BT injections.
Botulinum toxin injections are not only physically painful but also a frequent source of anticipatory anxiety and stress for patients with spasticity. Studies have shown that up to 60–70% of patients report significant injection-related stress or anxiety, which can negatively affect their adherence to long-term treatment and overall quality of life [1,3]. Although pharmacological anxiolytics may help reduce stress, their routine use is limited by risks of sedation, drug interactions, and adverse effects, particularly in patients with neurological comorbidities. Non-pharmacological approaches such as exercise, relaxation, or lifestyle-based interventions are beneficial in mitigating chronic stress and depression but remain impractical in the specific context of acute procedural stress during repeated injections [4]. Music-based interventions are hypothesized to be superior or complementary in this setting because they can be delivered immediately before and during the injection, are non-invasive, inexpensive, and easily adaptable to patient preferences. Moreover, receptive music therapy has demonstrated physiological effects on autonomic nervous system regulation, as reflected by improvements in Heart Rate Variability (HRV), suggesting its potential to reduce acute stress responses in painful medical procedures. Together, these elements support the rationale for evaluating music intervention as an adjunct to botulinum toxin injections for spasticity management.Stress-related body reactions are induced by the autonomic nervous system. Stress can be objectively assessed using biomarkers such as HRV [5]. Heart rate measurement is non-invasive, painless, easy to perform, and reproducible [6]. It reflects the cardiovascular response to regulatory impulses affecting heart rhythm [7]. Heart rate variability is a reliable indicator of autonomic nervous system activity [8], and numerous studies have employed HRV to estimate mental stress [9–12].
Since ancient times, music has been used to treat various ailments [13]. Reintroduced for therapeutic purposes in the 1960s, musical interventions have since been employed to alleviate pain and distress in patients with a range of medical conditions, particularly in the treatment of chronic and acute pain [14,15]. A recent meta-analysis found that musical interventions had positive effects on pain intensity, emotional distress, the use of anesthetics and opioid and non-opioid agents, heart rate, systolic and diastolic blood pressure, and respiratory rate [16]. However, contradictory results have been reported, likely due to the wide variability in musical interventions across different studies, which vary in terms of duration, frequency, style, genre, preparation, selection, and method of implementation [16]. To address these inconsistencies, recommendations have been formulated for the use of musical interventions in clinical practice [17,18]. In line with these guidelines, a standardized musical intervention based on a web application was developed at the University Hospital Center of Montpellier. This intervention follows a U-shaped composition sequence lasting 20–60 minutes, structured in several stages designed to gradually guide the patient into relaxation according to the U-technique [19]. The application allows for controlled use by the patient and/or caregiver at the bedside via a tablet. Based on the U-sequence, the Music Care program provides access to a range of music tracks pre-recorded by professionals in music therapy, musicians [20].
Several studies have focused on stress management, pain reduction, anxiety relief, and improving quality of life in patients with various pathologies and painful conditions, including cataract surgery [21,22], migraine treatment [23], coronary angiography [24], and cancer treatment [25].
To our knowledge, no clinical trials have examined the use of music interventions in conjunction with BT injections for the treatment of spasticity. The aim of this study is to investigate the effect of a music intervention session during BT injections on injection-induced stress. Our research team previously investigated another analgesic technique using virtual reality during BT injections in a separate study [26].
We hypothesize that a receptive music intervention can reduce the stress caused by BT injections in adults.
Methods and analysis
Study design and setting
We will conduct a prospective, interventional, randomized controlled trial in the Physical and Rehabilitation Medicine (PRM) department of the Clermont-Ferrand University Hospital, France. Recruitment for this study began on 25/04/2025.
Participants will be assigned to one of two groups: control or experimental. The control group will follow a waiting-list design, meaning participants in this group will receive the music intervention during their second injection. Each patient will serve as their own control, undergoing a first standard injection session without the music therapy device but with the heart rate sensor in place.
This study protocol presented in the S1 File, is reported in accordance with the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guidelines, presented in the S2 File [27]. The study results will be reported following the Consolidated Standards of Reporting Trials (CONSORT) Statement for non-pharmacologic trials [28]. Interventions are described in detail according to the Template for Intervention Description and Replication (TIDieR) checklist [29]. The provisional study schedule is shown in Figs 1 and 2.
Ethics and disemination
The study protocol was approved by the Medical Ethics Committee of Sud-Méditerranée IV and the Agence Nationale de Sécurité des Médicaments et des Produits de Santé (ANSM) the French National Agency for Medicine and Health Product Safety on March 4, 2025 (No. 25.00156.000468). All participants will provide written informed consent prior to enrollment, and the study will be conducted in accordance with the principles outlined in the Declaration of Helsinki.
Participants will be informed of their right to withdraw from the study at any time, in accordance with Good Clinical Practice guidelines and the French regulatory framework. Premature withdrawal may also occur due to intercurrent illness, death, significant protocol deviations, or loss to follow-up. Any adverse events reported during the study will be promptly communicated to the principal investigator to ensure timely action in safeguarding participants’ health. Data confidentiality will be strictly maintained, with robust measures in place to protect participants’ identities.
Any protocol modifications affecting study conduct, participant safety, or potential benefits will require formal approval through an amendment process by the CPP (French Medical Ethics Committee) Sud-Méditerranée IV to ensure continued compliance with ethical standards.
The study findings will be disseminated through peer-reviewed publications and presentations at scientific conferences.
Participants
Eligible participants for this study are adult patients, male or female, with neurological related spasticity, such as that resulting from multiple sclerosis, stroke, or traumatic brain injury, who are candidates for BT injection treatments. Participants may have undergone previous BT injections. Participants must have a known history of pain and/or anxiety and be capable of providing informed consent to take part in the research. Additionally, they must be affiliated with the French Social Security insurance scheme.
Patients with contraindications to musical interventions, such as severe hearing impairment, unstable psychotic disorders, or a history of auditory trauma will be excluded. People with major cognitive disorders and any other medical condition deemed incompatible with the study by the investigator will result in exclusion. Patients requiring sedation with nitrous oxide during BT injection sessions will not be eligible. Additionally, medications or with medical conditions that may interfere with HRV, such as beta-blockers, antiarrhythmics, anxiolytics, benzodiazepines, antihypertensives, and calcium channel blockers, will be considered exclusion criteria. Pregnant or breastfeeding women, as well as individuals who decline to participate, will also be excluded.
Recruitment
Participants will be recruited from the PRM departments of Clermont-Ferrand University Hospital in France. The Clinical Research Associate (CRA), in collaboration with the study investigators (physicians), will verify the eligibility criteria of patients followed in the department. Information about the study, along with an information sheet, will be provided to eligible patients 1–3 months before the inclusion visit, allowing them sufficient time to consider participation. For patients under protective measures, their guardian or curator must be present to review the information sheet. During the inclusion visit, individuals and/or their relatives will inform the team of their decision to participate or not. If both the patient and their relatives agree, the written consent form will be signed by the patient and/or their legal guardian or curator, as well as by the study investigator. The study is currently underway and in its recruitment phase. Recruitment of participants is expected to be completed by July 2027. Data collection is expected to be finalised by October 2027, with the study results anticipated for 2028. None of these steps have been completed to date.
Randomization
Participants will be randomized (1:1) into the experimental or control group during the first consultation. Block randomization with varying block sizes will be used. The randomization will be carried out by the CRA using RedCap (Version 8.2.50).
Interventions
All participants will undergo a first injection session without the Music Care application, wearing a Polar H10 heart rate monitor. The second session will be performed 3–4 months later as is standard practice for BT injection. All participants will wear a Polar H10 heart rate monitor. They will either use the Music Care application or not, depending on their group allocation.
Intervention group
The Music Care application is a receptive musical intervention in which patients select music based on their personal preferences from a variety of styles available on a tablet. A single, individualized music session is administered during the BT injection session. The music is played through headphones, in a calm environment conducive to relaxation. The standard musical sequence, lasting 20–60 minutes, is structured in several phases designed to gradually induce a state of relaxation, following the “U-sequence” method. This U-shaped sequence involves a progressive decrease in musical tempo, orchestral intensity, frequencies, and volume (the downward phase of the U) until a period of maximum relaxation (the bottom of the U) is reached. This is followed by a gradual recovery phase (the upward segment of the U) [19]. The U-sequence method is illustrated in Fig 3, reprinted with persission from Guétin and Touchon (2012) [20], provides a standardized framework for receptive music therapy. All musical sequences, designed according to this method, were recorded by Music Care (Paris, France).
Reprinted from Guétin S, Touchon J. The effects of music intervention in the management of chronic pain: a single-blind, randomized, controlled trial. Clin J Pain. 2012 May;28(4):329−37. https://doi.org/10.1097/AJP.0b013e31822be973. PMID: 22001666., under a CC BY license, with permission from Clinical J Pain, original copyright 2012.
To ensure reproducibility and standardization of the intervention, individual music preferences are collected prior to the session through a brief questionnaire on musical tastes. Patients then select a track from the Music Care application, which follows a standardized “U-sequence” format. Each track is based on a validated template, with predefined phases (progressive deceleration of tempo, orchestral intensity, frequencies, and volume, followed by a recovery phase). Thus, while the patient can choose the musical style, the therapeutic structure remains constant across participants.
The listening volume is systematically adjusted to mask surrounding procedural noise, ensuring immersion, while preserving auditory comfort and safety. The tempo is not modulated by the investigator, as all tracks inherently comply with the U-sequence structure. The chosen track is recorded in the Case Report Form (CRF). Patients are instructed to listen to the sequence in its entirety, regardless of injection duration. Adherence is monitored: if a patient discontinues listening before completion, the reason and timing are documented in the CRF as a deviation.
Consistency of delivery is ensured by standardized use of a tablet and headphones in a quiet setting. Technical fidelity is monitored at each session, with contingency procedures (e.g., spare headphones/tablets available) to address potential technical failures. These elements align with the TIDieR framework for intervention description, ensuring reproducibility and fidelity across participants [29].
No pain medication beyond the patient’s usual prescription will be permitted during the procedure.
During the injections, the same protocol will be consistently applied for each participant: either ultrasound or electrostimulation will be used to guide the injection, a MYOBOT needle will be used, and ice analgesia will be administered for palmar and plantar injections.
Control group
The control group will not receive any specific intervention, apart from the use of the Polar H10 heart rate monitor. Participants in this group will undergo BT injections as routinely performed in the department, and they will undergo the same assessments as the group receiving the music intervention during both injection sessions.
Primary outcome
The primary outcome is the effect of the music intervention on stress, assessed through HRV during the first injection visit. This will be estimated by the variation in HRV measured before and during the BT injection session. Data will be collected using a Polar H10 heart rate monitor, exported to the Elite HRV application (Version 5.5.8), and analyzed with KUBIOS software.
Secondary outcomes
The secondary outcomes include several aspects of the patient’s experience during the BT injection sessions. First, patient stress will be assessed again via HRV measured before and during the second injection visit. Pain intensity will be recorded during both the first and second injection visits using a numeric rating scale from 0 (no pain) to 10 (worst pain imaginable), immediately after each session. Anxiety levels will be evaluated using the State-Trait Anxiety Inventory Form Y-State (STAI-Y1) [30], a self-report questionnaire administered before and after both injection visits. The patient’s perception of time during the session will also be measured by comparing their subjective experience of time to the actual injection duration, with data collected at the end of each session. Patient satisfaction with the intervention will be assessed using a visual analog scale from 0 (very dissatisfied) to 10 (very satisfied), following both injection visits. Finally, the quality of the conditions for administering the BT injections will be rated by the physician immediately after each session, using a numeric scale from 0 (very poor condition) to 10 (very good condition).
Statistical considerations
Sample size estimation
To evaluate the effect of a music intervention session during BT injections on injection-induced stress, 35 patients per group will be required to detect an absolute mean difference in HRV of at least 1.8, with a standard deviation of 2.3 (sampsi program from Stata). This calculation assumes an allocation ration 1:1, a two-sided type I error of 5% and a statistical power of 90%. The absolute difference and standard deviation are based on findings from a previous study conducted by our team (Clinical Trials NCT05364203), in a similar context, specifically in patients with the same disease. In addition, several studies have reported effect sizes ranging from 0.5 to 1, which is consistent with the expected difference approximately 0.8 [31]. To account for potential dropouts or missing data (around 15%), a total of 40 patients per group is proposed.
Statistical analysis
All analyses will be performed using Stata software version 15 (StataCorp, College Station, TX, USA). Continuous variables will be presented as mean ± standard deviation or as median with interquartile range, depending on the data distribution. The assumption of normality will be assessed using the Shapiro–Wilk test.
At Injection Visit #1, the randomized groups will be compared in terms of eligibility compliance, epidemiological and clinical characteristics, and treatments. Baseline comparability between groups will be assessed using key participant characteristics and potential factors associated with the primary endpoint. Any observed imbalances will be interpreted based on clinical relevance. Protocol deviations, including their nature and the number of patients affected, will be documented along with the reasons for withdrawal. The number of enrolled patients and the inclusion flowchart will be reported by group.
Statistical analyses will be conducted primarily on the intention-to-treat population, including all participants except those who withdraw consent for data use. To minimize bias from informative missingness, appropriate imputation methods may be applied, depending on the extent and nature of the missing data (missing at random or not), i.e., considering both pattern and the amount of missingness. A secondary per-protocol analysis will be conducted, excluding participants who were not managed according to their assigned group or who had major protocol deviations. The type I error will be set at 5% (two-sided).
The primary objective is to assess the effect of exposure to a music intervention session during Injection Visit #1 on injection-induced stress, as measured by HRV. The primary analysis will compare the change in the low-frequency to high-frequency ratio (LF/HF ratio) of HRV between the randomized groups using Student’s t-test, or the Mann–Whitney U test if normality assumptions are not met. Equality of variances will be assessed using the Fisher–Snedecor F-test. Results for group comparisons will be reported as effect sizes with 95% confidence intervals. A multivariate analysis, such as multiple linear regression, will then be conducted to incorporate covariates identified through univariate analysis and clinical relevance (e.g., patient age and sex). Multicollinearity will be evaluated using Farrar and Glauber’s test and variance inflation factor indicators. Results will include regression coefficients (mean differences), effect sizes, and 95% confidence intervals. Subgroup analyses will explore the primary outcome by sex and age, examining group-by-subgroup interactions, with results reported in the same manner.
Secondary analyses will assess the effect of exposure to a music intervention session during BT injections at Injection Visit #1 on injection-induced stress (excluding the LF/HF ratio), pain, anxiety, patient satisfaction, and the physician-rated impact of the music intervention on the procedure. These analyses will follow the same statistical approach as used for the primary endpoint. To evaluate the effect of repeated exposure to the music intervention at Injection Visit #2, changes in stress, pain, anxiety, patient satisfaction, and physician-rated procedural impact will be analyzed using mixed-effects models. Longitudinal repeated measures will be modeled using random-effects models, which account for the fixed effects of group, time, and their interaction, as well as inter- and intra-subject variability. In particular, constrained longitudinal data analysis will be applied, using a mixed-effects linear model for continuous outcomes. This approach incorporates both baseline and follow-up data, with baseline group differences constrained to zero. Patient and time were treated as random-effect. More precisely, random intercept and slope effects at the patient level will be included, and model parameters will be estimated using restricted maximum likelihood. Model fit was compared across nested models using likehood ratio tests and information criteria (AIC and BIC). The selected model provided the best trade-off between goodness-of-fit and parsimony. Within-group analyses will also be conducted. For categorical outcomes, generalized linear mixed-effects models with a logit link and a constrained longitudinal data analysis framework will be applied to estimate odds ratios at follow-up, adjusted for baseline, with random effects modeled similarly. Non-repeated data will be analyzed using Student’s t-test or the Mann–Whitney U test for continuous variables (e.g., patient satisfaction), depending on normality and variance assumptions, and the chi-square test or Fisher’s exact test for categorical variables.
Discussion
This study aims to assess the effects of a receptive musical intervention on stress during BT injections for spasticity in adults. The anticipated benefit for patients is improved tolerance of the injection procedure. Recent work on temporal patterns of suicidal behaviour demonstrated that heightened vulnerability often coincides with periods of isolation and psychological strain [32], further underscoring the importance of integrating non-pharmacological strategies, such as music therapy, to mitigate stress in vulnerable populations and clinical settings. This translational perspective supports the incorporation of music-based interventions as a complementary approach in routine botulinum toxin injection protocols, particularly in rehabilitation medicine where repeated exposure to stressful procedures may otherwise compromise adherence and patient quality of life. Music intervention offers several advantages: it is non-invasive, non-pharmacological, low-cost, and easily accessible and portable. By helping to isolate the patient from the clinical environment, it enables the individual to focus on the musical experience and become distracted from the unpleasant stimuli of a stressful medical setting [33].
Although stress is an abstract concept, it can be quantified through HRV, which is sensitive to sympathomimetic influences and requires highly standardized conditions. In general, HRV is a reliable indicator of autonomic nervous system activity [8], and many previous studies have used it to estimate mental stress [9–12].
One limitation worth noting is individual variability in receptivity to music therapy. Responses may differ from one patient to another, potentially introducing a confounding factor. However, the sample size was calculated to account for this variability. Another possible limitation is the habituation effect patients who have been receiving this therapy for several years may experience less stress overall, which could influence the study outcomes.
Communication policy
Data will be disclosed only following prior mutual agreement between the investigator and the sponsor. The study results will be communicated and published in accordance with international publication guidelines (www.icmje.org). Authors affiliated with Clermont-Ferrand University Hospital will be listed as the first and last authors of the primary publication. The study will be registered on the ClinicalTrials.gov website.
Strengths and limitations of this study
- This study will be the first to assess the effects of a receptive music intervention on stress during botulinum toxin injections for spasticity in adults.
- In addition to being non-invasive and non-pharmacological, music intervention offers multiple advantages, including minimal adverse effects, low cost, and easy accessibility and portability.
- The study design aims to achieve the highest level of evidence through a prospective, randomized, controlled approach.
- Stress is an abstract concept and there is no gold standardfor its evaluation; in this study, it will be assessed indirectly through heart rate variability.
- Receptivity to music intervention may vary between patients, potentially acting as a confounding factor.
- A habituation effect may occur in patients who have been exposed to this intervention over several years, potentially reducing observed stress levels.
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