Pain Management Strategies for Botulinum Toxin Type A Injections in Children: A Comprehensive National Survey and Procedural Protocol

Introduction: Botulinum toxin type A injections are a first-line treatment for spasticity in children. Our purpose is to delineate the national landscape concerning pain management for botulinum toxin type A injections in pediatric patients and to formulate a protocol grounded in current scientific evidence. Methods: We conducted a nationwide survey targeting physical medicine and rehabilitation specialists performing botulinum toxin type A injections for focal spasticity in children in Portugal. We conducted a literature review to compare the survey results with clinical guidelines, good practice manuals, and protocols published in the literature. Finally, we developed a procedural protocol for pain management in botulinum toxin procedures. Results: The survey was completed by 17 out of 18 identified specialists. All but one use some form of periprocedural analgesia. Five do not use any type of sedation. The majority do not assess pain during the procedures. From the reviewed articles, we obtained 23 articles, 19 of which provided data for detailed analysis. Conclusions: A prevailing concern centers around pain management during botulinum toxin procedures in children. Nevertheless, a distinct absence of uniformity persists in appraising and managing procedure-related pain. This notion is further underscored by the marked heterogeneity and paucity of published literature within this realm. The systematic implementation of a procedural protocol thus becomes highly crucial.


Introduction
Botulinum toxin type A (BoNT-A) injections are a first-line treatment for focal, multifocal, and segmental spasticity in children [1,2].According to the Royal College of Physicians [3], the goals of BoNT-A intervention are pain control, reduction of involuntary movements, prevention of contractures and deformities, improvement of passive and/or active functions, and enhancement of mobility, including gait.Achieving these goals involves the periodic administration of BoNT-A to maintain the benefit and prevent or delay the development of irreducible contractures.In most cases, the infiltration of several muscles per session is necessary, as most children exhibit spasticity in multiple segments [4].
The guidance method for the injections, as well as the pain management strategy during the procedure are two aspects that should be considered when administering BoNT-A to children [2,4].There are several guidance methods available, including palpation, anatomical landmarks, electromyography, electrical stimulation, and ultrasound [4].Among these, ultrasound is a real-time dynamic imaging method with excellent spatial resolution and safety profile, and it has been the preferred method in studies with pediatric populations [4,5].
According to the Portuguese Directorate General of Health [6], invasive procedures are the most frequent cause of pain in children seeking healthcare services, often together with fear and anxiety.These factors worsen the pain, underscoring the importance of minimizing anticipatory anxiety through a comprehensive pain management approach right from the initial interaction with healthcare services [6].Taking this into consideration, it becomes imperative to formulate and implement a suitable protocol for pain management aimed at mitigating the pain and anxiety linked to BoNT-A injections [2].This protocol should consider not only analgesia strategies but also pain assessment [6].
Sedation is mostly employed to alleviate pain and anxiety, thus promoting the child's cooperation and ensuring the safe execution of the procedure.The child's capacity to control their behavior and cooperate depends not only on their age but also on their level of cognitive and emotional development [7].In addition to pharmacological strategies, non-pharmacological methods should be applied, as they have the potential to reduce the requirement for more profound sedation, especially in minor and brief procedures [6,7].Sedation of pediatric patients involves some risks, which become more pronounced in children with developmental impairment.These children, when exposed to sedative drugs during invasive procedures, exhibit an incidence of hypoxia three times higher compared to children without developmental impairment [8].Appropriate drug selection, a comprehensive grasp of their pharmacokinetics, pharmacodynamics, and potential interactions, along with the presence of a physician skilled in advanced pediatric life support, collectively assume a vital role [7].
While clinical guidelines and protocols exist for sedation and analgesia in therapeutic or diagnostic procedures [2,6,7,9], the authors have found a gap concerning their application and standardization in procedures involving BoNT-A injections in children.There is a notable scarcity of publications in this field.Furthermore, there is no published data in Portugal regarding the assessment and management of pain from BoNT-A injections in children.
This study aims to outline a procedural protocol for the effective management of pain during BoNT-A injections in pediatric patients.This proposal is grounded in an understanding of the real-world clinical practices across different centers in Portugal, as well as the information outlined in the literature.

Materials And Methods
We conducted a nationwide multicenter survey targeting all physical medicine and rehabilitation (PM&R) specialists practicing in Portugal who use BoNT-A for the treatment of spasticity in pediatric patients.We juxtaposed the obtained results with existing literature and devised a protocol proposal for evaluating and addressing pain during BoNT-A injections in children.

Development of the nationwide multicenter survey
We designed the survey based on our clinical practice, anchored in clinical guidelines, best practice manuals, and protocols published regarding the use of BoNT-A for the treatment of focal spasticity in children [1,4], alongside considerations for periprocedural pain management [2,6,7,9].The survey was divided into two parts: an initial section for sociodemographic and clinical characterization of the PM&R specialist and a second section focused on BoNT-A injections in focal spasticity in children (Figure 1).

FIGURE 1: A survey was conducted with PM&R specialist, who currently perform BoNT-A injections in children as part of their clinical practice in Portugal
BoNT-A: Botulinum toxin type A; FIM: Functional independence measure; EMG: Electromyography; FLACC: Face, legs, activity, cry, consolability

Participant selection and survey administration
We identified all PM&R specialists working in pediatric rehabilitation in Portugal who currently perform BoNT-A injections in children as part of their clinical practice.Their contact information was obtained through the interest group "Pediatric Rehabilitation Section of the Portuguese Society of PM&R," through which the survey was shared in an online format using the Google Forms® application.
We excluded PM&R specialists who exclusively perform BoNT-A injections in adults.Medical residents, neurologists, pediatricians, and anesthesiologists were also excluded.
We conducted a descriptive analysis of the results using Microsoft Excel® software.Specific cases and/or comments were also subjected to analysis and are presented when deemed relevant.

Literature review
We conducted a literature review by searching the MEDLINE (PubMed) and Cochrane Library databases.We used the search terms ((botulinum toxin) AND (children)) AND ((best clinical practices) OR (protocol) OR (guidelines)) and ((botulinum toxin) AND (children)) AND ((analgesia) OR (sedation)).Additionally, the reference lists of selected articles were analyzed to identify relevant papers that might not have been obtained in the initial search.Only articles published within the last 15 years were included, with no language-based exclusions.The acquired articles were imported into the Mendeley® reference management software, where duplicate documents were automatically removed.In the initial stage, articles were selected based on their titles; in the second stage, abstracts were read; and in the third and final stage, articles were read in their entirety.Articles that did not address pain assessment and/or management, as well as those not involving BoNT-A injections, were excluded from the final review (Figure 2).The review was conducted in November 2022.For the obtained articles, we created a form with the most relevant topics to extract: first author, year of publication, study design, main goal, population, sedation and analgesia, adverse effects, nonpharmacological strategies, pain assessment, and main conclusions.We employed this form as a tool for detailed and comparative analysis of the extrapolated data.

Nationwide multicenter survey
The survey was available for 33 days, from October 12th to November 13th, 2022, and was completed by 17 out of total 18 identified specialists (94%) (Table 1).Out of the 17 responses, two were excluded: one was disregarded because the specialist did not employ BoNT-A in children, and the other because the specialist did not employ BoNT-A for treating focal spasticity.The collected responses showed geographical representation throughout the country, encompassing regions from north to south, including the islands.Of the respondents, 53.3% (n=8) dedicate at least one weekly session (morning or afternoon) of their clinical practice to focal spasticity treatment in children using BoNT  All specialists (n=15) employ the Modified Ashworth Scale for spasticity assessment.Additionally, 86.7% (n=13) evaluate joint ranges of motion, and 33.3% (n=5) complement their assessment with the Tardieu scale.Other methods for functional assessment include the Functional Independence Measure (20%, n=3), Timed Up and Go (13.3%, n=2), Goal Attainment Scaling (13.3%, n=2), and the 10-meter walk test (13.3%, n=2).All specialists (n=15) use onabotulinumtoxinA, 93.3% (n=14) use abobotulinumtoxinA, and 26.7% (n=4) use incobotulinumtoxinA.Among them, 6.7% (n=1) solely use onabotulinumtoxinA, 66.7% (n=10) use two toxins (onabotulinumtoxinA and abobotulinumtoxinA), and 26.7% (n=4) use all three toxins (onabotulinumtoxinA, abobotulinumtoxinA, and incobotulinumtoxinA).The dilution and maximum dosage utilized are contingent upon the chosen toxin for the procedure.Sixty percent (n=9) use ultrasound as a guidance method, while the remaining 40% (n=6) use anatomical references and/or palpation.

Literature review
From the conducted research, we obtained 23 articles for review, the majority of which were published in journals ranked in the first or second quartiles (78%, n=18) in their respective years of publication.Out of the 23 articles, 12 (52%) were published in the last four years (since 2018), and the majority (n=21) were written in English.We obtained four randomized controlled trials, eight prospective studies, seven retrospective studies, one cross-sectional questionnaire, one literature review, one clinical guideline, and one commentary.Due to the significant heterogeneity among the articles, we could not conduct a metaanalysis.However, it was possible to extrapolate data for analysis and comparison among 19 out of the 23 articles obtained (Table 2).Patel [   The sample sizes were very different among the studies, with variability ranging from n=10 to n=758 and an average sample size of 120 children with a mean age of 8.36 years old (min.3.79; max.14.67).In 19 studies, the included children had cerebral palsy (CP), while in the remaining four studies, no information was provided regarding the underlying pathology.Among these 19 studies, 10 characterized their samples according to the Gross Motor Function Classification System (GMFCS), showing a balanced distribution across levels I-IV (level I/II x=36, level III/IV x=35) and a lower frequency for level V (x=7).Six out of the 23 studies (26.1%) included other pathologies such as stroke, traumatic brain injury, and mitochondrial diseases.
Among the studies that investigated pharmacological strategies for pain control during BoNT-A injections in children (n=15), the most studied drugs were midazolam (n=8), nitrous oxide (n=7), ketamine (n=4), and sevoflurane (n=2).A topical anesthetic was used in combination with other drugs in eight out of the 15 studies.Of these 15 studies, all except one [10] analyzed the efficacy of nitrous oxide prospectively.When compared to midazolam, nitrous oxide appeared to be more effective and allowed for quicker recovery [11], and it was considered a better option when used in cooperative children without comprehension impairment [12].Nitrous oxide, in combination with EMLA®, was effective in only half of the children in the studies by Brochard et al. and Gambart et al. [13,14].Forrester et al. concluded that conscious sedation with nitrous oxide in combination with a local anesthetic could be a viable alternative to general anesthesia [15].On the other hand, Cantador-Hornero et al. found that patients who received deep intravenous sedation experienced significantly less pain compared to others (absence/topical anesthetic cream, nitrous oxide, and oral or enteral benzodiazepine) [2].León-Valenzuela et al. retrospectively studied the efficacy of sevoflurane and concluded that a sedation protocol with sevoflurane resulted in a high effectiveness rate in pain control during BoNT-A injections, being successful in 100% of cases [10].
Regarding adverse effects, in the studies where they were listed (n=13), all authors acknowledged nonserious and transient adverse effects when they occurred.The most frequently described adverse effects were nausea, vomiting, and hypoxemia.Concerning hypoxemia, it was reported in all studies as transient and immediately resolved with oxygen therapy.Zier et al. reported oxygen levels below 92%, which were promptly and incident-freely resolved by administering 100% oxygen [11].
The non-pharmacological strategies were employed in combination with sedative and analgesic drugs in five of the studies, with distraction techniques being the most reported.Four of the selected studies examined the impact of non-pharmacological strategies on periprocedural pain control, specifically virtual reality (n=2), biofeedback-assisted relaxation training (n=1), and the presence of child life specialists (n=1).All of them reported positive outcomes in terms of alleviating pain and anxiety.
In most studies (n=14), pain and/or anxiety related to the procedure were assessed.The most used pain assessment scales were the FLACC scale (n=5), the VAS (n=5), and the Faces Pain Scale/Faces Pain Scale Revised (n=5).Likert-type scales for evaluating satisfaction and/or pain perception from parents or healthcare professionals were also used (n=5).

Discussion
The results obtained from conducted survey demonstrate a clear concern among specialists about managing the pain caused by BoNT-A injections in pediatric patients.However, there is a noticeable lack of standardization in both pain control and assessment during the procedure.Similarly, the significant heterogeneity and limited number of published studies on the topic reinforce this notion and restrict the establishment of measures to optimize clinical practice.The utilization of analgesia strategies appears to be unanimous and already widely implemented.However, the absence of a formal pain assessment during the procedure prevents conclusive insight into the effectiveness of the employed strategies.Moreover, procedures of this nature induce anxiety and fear in children, which could contribute to procedural failure and elevate their risk.Hence, sedation, by mitigating these factors, assumes significant importance.As observed, a noticeable gap exists in this regard as well, with one-third of Portuguese PM&R specialists not using any sedative agents.When we compare the questionnaire results with the findings of the conducted research, it becomes evident that the most frequently used drugs by Portuguese PM&R specialists are also those frequently mentioned in the literature, notably nitrous oxide, sevoflurane, and midazolam.Similarly, there is concurrence in the pain assessment scales employed, particularly the FLACC scale, VAS, and Faces Pain Scale/Faces Pain Scale Revised.
Most studies included children with cerebral palsy or other neurological conditions, and they concluded in favor of the efficacy and safety of the studied drugs, describing only non-serious and transient adverse effects.
Guidelines for analgesia and sedation in children undergoing procedures for therapeutic or diagnostic purposes are available [6,7], which serve as a guide for more specific procedures, such as BoNT-A injections.However, these guidelines should be adapted, considering the particularities of these children and the procedure itself.
The medical team should include a PM&R specialist responsible for performing the procedure, an anesthesiologist responsible for managing analgesia and sedation during the procedure, and a nurse, preferably with experience with pediatric patients [7].The presence of an anesthesiologist adds technical and scientific quality to the team while allowing the physician responsible for administering BoNT-A to focus solely on the procedure.
The chosen place for its execution will depend on the available resources and, simultaneously, will influence the pharmacological and non-pharmacological strategies to be adopted.Options such as the consultation office, treatment room, or operating room are all valid choices.However, it is imperative that these facilities are outfitted with all the essential supplies commensurate with the level of sedation and the drugs intended for use.This includes access to an oxygen supply, an exhaust or gas scavenging system, vital sign monitoring, and a pediatric emergency cart/kit [7].
The choice of pharmacological strategies for pain management will be contingent on various factors, including the targeted sedation level, the child's age and cooperation capacity, and the available material and human resources.The literature appears to be unanimous in advocating the use of topical analgesia at the intended sites for BoNT-A injections.The most studied strategy involves the combination of lidocaine and prilocaine (EMLA®), to be applied 45 to 60 minutes before the procedure.This local analgesia should be complemented by systemic sedatives and/or analgesic drugs.When targeting minimal or moderate sedation ("conscious sedation"), especially in older children who are cooperative and have no comprehension impairment, midazolam and inhaled nitrous oxide are safe and effective options.Between these two, inhaled nitrous oxide should be preferred over midazolam in cooperative children due to its faster onset and recovery time.However, some studies have shown only 50% effectiveness with the combination of nitrous oxide and EMLA® in children undergoing BoNT-A injections, suggesting that the addition of another analgesic drug might be necessary [13,14].Children under four years might not tolerate inhaled nitrous oxide, making midazolam a preferable option in these cases.The combination of midazolam and ketamine seems to enable the reduction of the required dosage for both drugs to attain the intended sedative and analgesic outcomes, all while maintaining a high level of safety [16].For deep sedation, particularly in younger and/or uncooperative children, propofol and ketamine alone or in combination, as well as sevoflurane, could be the best choices.When using ketamine, the prophylactic administration of ondansetron may reduce the occurrence of post-procedural vomiting.The combination of propofol with ketamine appears to be effective and associated with a lower risk of vomiting and hypotension compared to using ketamine alone [22].Sevoflurane has demonstrated safety and effectiveness, with the advantage of being administered through inhalation and exhibiting good tolerance.It is a suitable choice for performing multi-level injections, as it allows for exploration under sedation [10].
Considering the lack of literature data on preferred drug administration routes, opting for less invasive routes of administration over intravenous and intramuscular methods appears reasonable.
Non-pharmacological strategies should be systematically used and selected according to the child's age and developmental level.For infants, breastfeeding and non-nutritive sucking are recommended.In younger children or those with comprehension impairment, 30% glucose or 24% sucrose solutions, local massage, and distraction techniques such as videos, games, stories, or books are the most suitable and effective strategies.For older children without language or cognitive impairments, prioritizing dialogue and explaining the procedure to them is important.Strategies like positive reinforcement, behavioral modeling, guided imagery or hypnoanalgesia, and muscle relaxation and/or breathing exercises before and after the procedure are appropriate [6].Other strategies, such as virtual reality, biofeedback-assisted relaxation training, and the presence of Child Life specialists in the room, have been studied and have shown increasing effectiveness in pain control during procedures [18,20,23,29].
Maintaining pain intensity below 3/10 (mild pain) is considered a criterion for high-quality pain control [30].Therefore, it is imperative to integrate pain assessment scales tailored to the child's age and developmental stage into the procedural protocol.If the child is under four years old or unable to verbalize, the FLACC scale should be used.For children aged 4 to 6, the Faces Pain Scale and Faces Pain Scale-Revised are more appropriate.For those over six years old, the suitable scales are VAS and NRS.For children with multiple disabilities, the FLACC-R scale is recommended [30].Given the absence of established optimal timing for pain assessment in existing literature, the authors propose the following approach to evaluating pain: utilizing behavior-based scales during the procedure and employing self-report scales immediately afterward.
Vital signs should be continuously monitored throughout the entire procedure [7].For any procedure requiring sedation, proper preparation is indicated.This includes an appropriate fasting period (2 hours for liquids, 4 hours for breast milk, and 6 hours for light meals), a medical evaluation with a focus on the airway, the American Society of Anesthesiologists (ASA) classification, and a review of anesthesia history [7].Before the procedure, informed consent should be provided to parents or responsible caregivers for their full reading and authorization of the procedure.
Based on the results and premises presented, the authors propose a pain control protocol (Figure 3).According to the authors' knowledge and up to the current date, this is the first study aiming to propose a procedural protocol not only for pain management in BoNT-A injections in children but also for its systematic assessment.This is based on the characterization of current national clinical practice and the analysis of published evidence.The application of a non-validated survey designed for a very specific purpose and directed only at PM&R specialists, as well as the restriction of search criteria to papers published within a predetermined period that specifically refer to pain control in BoNT-A procedures, are limitations of this study.

Conclusions
This study follows the principles of the Declaration of Helsinki.The completion of the survey was considered 2023 Moreira et al.Cureus 15(11): e48311.DOI 10.7759/cureus.48311the participant's consent.The questionnaire was filled out anonymously, and the collected data were treated confidentially.
the safety and efficacy of midazolam, ketamine and intranasal fentanyl in children undergoing BoNT-A injection.
older children (>5 years old) who can comply with verbal instructions and require a limited number of injections, selfadministered Entonox ® can provide a similar level of procedural pain control to the continuous flow nitrous oxide ⁄oxygen system used by Zier et al.It has other advantages in terms of potentially fewer adverse effects and lower resource overheads.recommend the use of GA to optimize BoNT-A treatment in patients with CP.This approach facilitates the assessment of contractures and enables the use of electrostimulation.Forrester[15] 2012 Prospective study Comparing carer satisfaction and perception of procedure related pain and distress for intramuscular BoNT-A injections administered to children and adolescents with CP using 2 methods of analgesia / sedation: conscious sedation using nitrous oxide and topical local anesthetic versus general anesthesia n=171 (age x=7,08); children with CP: conscious sedation group (1) with homogeneous distribution across the 5 levels of GMFCS.; GA group (2) with a predominance of GMFCS II and III.distress by caregivers and physicians during entry into the procedure room and mask placement was similar with conscious sedation and GA.The pain perceived by caregivers caused by the procedure under conscious sedation was significantly greater than under GA.There was no significant difference in overall satisfaction with either modality.Comparing the efficacy of sedation n=50 (age x= 8,17 (1-16)); children with CP: group 1 GMFCS I n=0, II n=13, III=3, IV=6, V=3; hemiplegia=8, midazolam, but those who received nitric oxide were less sedated at the end of the procedure; nitric oxide more effective in reducing pain than midazolam; parents expressed 2023 Moreira et al.Cureus 15(11): e48311.DOI 10.7759/cureus.ofclinical practice in relation to the use of BoNT-A in the management of muscle spasticity in children.n=758 (age x=9,04); children with CP (94%), Stroke, from 17 centers: none in 6; GA in 4; local anesthetic and/or midazolam in 7. The study shows that infiltrations can be performed without GA in most cases.

FIGURE 3 :
FIGURE 3: Procedural protocol for pain assessment and management in BoNT-A injections in children.Consult.Room: Consultation room; PO: per os; FLACC-R: Face, legs, activity, cry, consolability-revised; FLACC: Face, legs, activity, cry, consolability; FPS-R: Face pain scale-revised; VAS: Visual analog scale; NRS: Numerical rating scale.a) Equipped with oxygen supply, vital sign monitor, and emergency cart/kit; b) Preferred approach; c) During and/or immediately after the procedure