I-STRONG: an integrative, multicomponent treatment approach for chronic pain in pediatric sickle cell disease

Key Points

• •I-STRONG is an integrative, multicomponent treatment program that may reduce chronic sickle cell pain.
• •Community engagement strategies increased the feasibility and acceptability of I-STRONG through population-specific adaptations.

Visual Abstract

Abstract

Chronic pain affects ∼20% of adolescents living with sickle cell disease (SCD). There is a critical unmet need for evidence-based interdisciplinary approaches for chronic SCD pain treatment. We aimed to (1) use community engagement to adapt an integrative multicomponent treatment program designed to meet the unique needs of chronic SCD pain (ie, Integrative Strong Body and Mind Training [I-STRONG] for SCD), and (2) optimize feasibility and acceptability of I-STRONG through a proof-of-concept trial. Modifications to an existing cognitive behavioral therapy (CBT) and neuromuscular treatment program for chronic widespread pain were informed by semistructured qualitative interviews with adolescents (aged 12-18 years) with chronic SCD pain (n = 12) and their caregivers (n = 12), community advisory boards, and interdisciplinary experts to develop I-STRONG. I-STRONG is a virtual 8-week, 16-session, group intervention combining CBT and neuromuscular exercise training, co-led by experts in psychology and physical therapy. A pilot clinical trial of I-STRONG (n = 12 adolescents; n = 9 caregivers) was conducted to iteratively optimize intervention feasibility and acceptability. Community engagement strategies informed systematic adaptations for access, engagement, relevance, satisfaction, and sense of belonging to meet the unique needs of youth experiencing chronic SCD pain. Pilot testing demonstrated high levels of feasibility (95% completion, 97% intervention fidelity, 92% retention), moderate to high acceptability, and safety. Over 82% of adolescents reported improvements in pain after treatment and at 3-month follow-up. Preliminary evidence suggests that I-STRONG is a promising approach for management of chronic pain in pediatric SCD. A planned multicenter, randomized controlled trial will evaluate I-STRONG’s efficacy for pain reduction. This trial was registered at www.clinicaltrials.gov as #NCT06110754.

Introduction

Recurrent acute pain is the hallmark feature of sickle cell disease (SCD), a group of rare inherited blood conditions that disproportionately affect African Americans in the United States. Approximately 23% of children and adolescents with SCD also experience chronic pain.1, 2, 3 Chronic SCD pain in youth is associated with functional impairment, depressive symptoms, sleep disruption, and more frequent hospitalization, leading to missed academics and social opportunities.^4,5

Chronic SCD pain is most effectively managed by interdisciplinary, individualized treatment including nonpharmacological and integrative interventions,⁶ yet multicomponent approaches specifically for chronic SCD pain are not yet established. Individually, opioids, cognitive-behavioral interventions, and movement-based interventions (eg, physical therapy, yoga, physical activity, exercise) produce modest short-term improvements for individuals with chronic pain.6, 7, 8, 9 For example, pharmacological therapies for chronic SCD pain have small, variable effects on sustained pain reduction.⁶ Cognitive behavioral therapy (CBT) has been shown to be effective for pain reduction and functional improvement in pediatric chronic pain, yet the evidence for chronic SCD pain specifically remains sparse.^6,7,10, 11, 12 Similarly, movement-based interventions (eg, facilitated exercise training, physical therapy) are feasible and acceptable to individuals with SCD¹³ and commonly recommended for SCD pain with musculoskeletal dysfunction and early stages of avascular necrosis to protect joint health,^14,15 yet there is limited evidence of improved outcomes in pediatric SCD¹⁶ and uptake is variable due to limited access, perceived lack of benefit, or worry about increased pain.¹⁷ To better align with the biopsychosocial model of pain, interventions need to integrate pain medicine, psychology, and physical therapy to target underlying pain-related worries and activity avoidance to effectively address pain chronicity and functional impairment, and to achieve a clinically significant benefit.18, 19, 20, 21

In the absence of a well-developed evidence-base for chronic SCD pain treatment, the American Society of Hematology identified fibromyalgia as most closely aligned with chronic pain in SCD (with no identifiable cause beyond SCD) to inform conditional treatment recommendations.⁶ In juvenile fibromyalgia, an innovative multicomponent intervention that combined CBT and neuromuscular exercise training (Fibromyalgia Integrative Training for Teens [FIT Teens]), demonstrated medium to large effects on reducing functional impairment, depressive symptoms, and fear of pain in clinical trials, with significantly greater reductions in pain than CBT alone.²² Neuromuscular training is a specialized form of exercise targeting functional movement and dynamic strength stabilization to gradually enhance body awareness, strength, and control. Because it primarily relies on body-weight resistance and movement training with little equipment, it is more accessible and easily integrated with CBT for pain to support psychological coping. By combining CBT for pain with neuromuscular exercise training, adolescents gain opportunities for pain and coping education, practice, and social support, all of which are critical themes identified by youth with SCD to support physical activity.²³

There are many unique experiences of chronic SCD pain, such as condition-related stigma, concerns about inadequate pain treatment,²⁴ knowledge about disease management based on lived experience,²³ and the intersection of chronic pain that may or may not be complicated by SCD,² that require community partnership to inform interventions specifically designed to support patients with SCD to ensure feasibility and acceptability.^2,25,26 This study aimed to (1) partner with adolescents with chronic SCD pain and their caregivers to modify and refine the integrative components of the existing combined CBT and neuromuscular exercise intervention to target the unique needs and preferences of families managing SCD and chronic pain; and (2) iteratively develop and test the feasibility and acceptability of Integrative Strong Body and Mind Training (I-STRONG), the new, integrative intervention for youth with chronic SCD pain, in a single-arm proof-of-concept trial.

Methods

Study design and intervention modification framework

This study occurred over 2 phases: intervention modification designed to target the unique needs of chronic SCD pain (phase A) and iterative optimization of intervention feasibility and acceptability through a single-arm pilot trial (phase B). I-STRONG was developed based on the FIT Teens program, an 8-week, 16-session, group-based CBT and neuromuscular exercise training interdisciplinary protocol, originally developed and tested for youth with juvenile fibromyalgia.²² A progressive neuromuscular exercise training approach was specifically selected because it is designed to limit delayed-onset muscle soreness, decrease pain catastrophizing, and flexibly allow individualization to patient need. The progression of muscle actions start with stabilizing through isometric training followed by creating movement; resisting movement; and finally, integration into functional movement.²⁷

Intervention modifications were guided by the ADAPT-ITT model,²⁸ a systematic framework to adapt existing treatments to new populations while maintaining fidelity to evidence-based interventions using a cyclical process to inform tailoring of content to meet the unique population needs. Modifications were informed by evidence from the literature on lived experiences of chronic SCD pain^29,30; patient and family treatment preferences^,31; semistructured qualitative interviews with adolescents with chronic SCD pain and their caregivers; community advisory board (CAB) input; and interdisciplinary experts representing hematology, psychology, physical therapy, rehabilitation medicine, and sports medicine. Modifications retained evidence-supported treatment components, with modification as appropriate to maximize feasibility, acceptability, and relevance for youth with chronic SCD pain.

Participants

Participants included adolescents, young adults, and their caregivers recruited within the SCD programs of 2 large children’s hospitals in the Southeastern and Midwestern United States. Recruitment occurred from June 2023 through January 2024. Inclusion criteria were age of 12 to 18 years, medium-to-high risk of chronic pain via the pediatric pain screening tool,³² and receiving stable SCD-related standard care (including disease-modifying medications or treatments, if applicable) over the preceding 3 months. Young adults aged 18 years could enroll with or without a caregiver. Exclusion criteria were comorbid medical conditions associated with pain unrelated to SCD (eg, rheumatological conditions), documented cognitive/developmental disabilities that would interfere with participation in the intervention, other contraindication for participation (eg, severe avascular necrosis with limited or non–weight bearing restrictions; phase B only), and those who were concurrently in a structured CBT or physical therapy program during the active treatment phase (phase B only). Participants were identified through purposive sampling to support representativeness across age and chronic pain risk for phase A.

Enrollment procedures

Study team members prescreened potentially eligible adolescents and approached them and their caregivers during clinic visits or by phone. The study was approved by a central institutional review board.

Phase A: intervention modification

A mixed-method approach was used to collect qualitative feedback informed by patient and family lived experiences regarding intervention content, format, perceived benefits, and barriers/facilitators to engagement with youth who have chronic SCD pain and their caregivers.

A CAB was convened for this study to be representative of persons with lived experience of SCD and chronic pain and their caregivers. CAB members included SCD community health workers from each site and adolescents with SCD and their caregivers who participated in phase A. The study team partnered with the CAB to inform protocol modifications to address the needs of youth with chronic SCD pain and their families (see supplemental Methods for details).

Participants were interviewed using a semistructured interview guide for 45 to 60 minutes via a secure videoconferencing platform, and were provided with the intervention protocol, materials, and recruitment materials, and were shown videos of the neuromuscular exercises. To enhance impact and dissemination of the modified intervention, the interview guide was informed by the RE-AIM (Reach, Effectiveness, Adoption, Implementation, Mainetenance) approach³³ to enhance the effectiveness and long-term sustainability of the intervention. Adolescents were interviewed either jointly with their caregiver or separately depending on family preference. Qualitative interviews were audio-recorded and professionally transcribed verbatim. A research study team member checked transcripts for accuracy by reviewing the recordings.

Measures

The Pediatric Pain Screening Tool³² was completed by adolescents and consists of 9 items intended to identify a patient’s risk status (high, medium, or low) of poor pain-related clinical outcomes using established biopsychosocial prognostic factors with validation among youth at risk for chronic SCD pain.³⁴ A total score ≥3 suggests medium to high risk of poor clinical outcomes related to pain (eg, moderate to severe disability, mild to moderate mood concerns) and was used to determine study eligibility to be inclusive of patients with poor pain-related outcomes commonly associated with chronic pain and risk for transition from acute to chronic pain.

The PhenX (consensus measures for phenotypes and exposures) toolkit SCD core (tier 2 collection)³⁵ was completed by caregivers to report SCD characteristics, school performance, and insurance coverage.

Pediatric demographics³⁶ including sociodemographic information was competed by caregivers or young adults.

Analytic strategy

Coders were experienced in qualitative data analysis (S.S., C.S., J.T.M., and N.B.). Analysis was conducted in MAXQDA³⁷ (S.S. and C.S.) using a hybrid deductive-inductive approach³⁸ and focused on identifying and addressing potential barriers to participation, representativeness of materials, appropriateness/applicability to the experiences of youth with chronic SCD pain, and feasibility of exercises and coping strategies, aligned with the main topic areas queried in the semistructured interviews. Of all transcripts, ∼25% were analyzed by a third coder (J.T.M.) to support intercoder reliability, yielding ≥90% agreement. An integration of qualitative results and CAB feedback supported revised intervention content, materials, and design.

Phase B: feasibility and acceptability testing

Procedures

Participants completed assessments before treatment, after treatment, and at 3-month posttreatment follow-up. Assessments included patient-reported outcome measures, prospective 7-day pain diary, caregiver-reported questionnaires, 6-minute walk test (6MWT), and 7-day physical activity monitoring via actigraphy. Questionnaires and diaries were completed via a secure web-based application. Assessments were administered by a research assistant who was not involved in treatment delivery.

After the pretreatment assessment, the active treatment phase included 16 group-based, 90-minute telehealth sessions delivered twice weekly over 8 weeks and 1 booster session scheduled 1.5 months after the final treatment session. At posttreatment assessments, participants completed qualitative exit interviews to share their perceptions and feedback for intervention optimization and refinement. Groups consisted of participants from the same recruitment site, and group size ranged from 3 to 6 adolescents. Based on participant and CAB feedback, iterative improvements were flexibly incorporated into subsequent groups to optimize and refine I-STRONG (see supplemental Methods for details). Families were compensated for time spent completing questionnaires and diaries, 6MWT, actigraphy, each treatment session, and exit interview.

I-STRONG intervention

Treatment materials were modified from an existing CBT protocol for adolescents with chronic SCD pain,³¹ the existing FIT Teens protocol,²² and participatory and CAB engagement as described in Phase A. The resulting new I-STRONG program for SCD treatment components are summarized in Table 1. The neuromuscular training protocol was specifically designed to reduce the potential for delayed-onset muscle soreness through gradual progression to new levels of exercise every 2 weeks, with close monitoring and constructive feedback to ensure participants used proper form before advancing to the next level. Coping skills were practiced while participants engaged in neuromuscular exercises for an integrated approach. Individualized homework plans were developed at the end of each session to support practice and integration of skills at home. Participants completed an electronic daily diary to monitor pain and related symptoms (eg, mood, sleep, fatigue) and adherence to home practice. Completed diaries were reviewed at the beginning of each session to support benefits of self-monitoring, review progress, and problem-solve barriers to skill integration into daily life. Per CAB feedback, caregivers and family members were welcome to attend all sessions with the adolescent and at least 6 sessions required caregiver participation for at least part of the session.

Table 1.

Final structure and content of I-STRONG intervention sessions

	Session (90 min total)	Mind-body and cognitive-behavioral skills training (45 min)	Neuromuscular exercise training (45 min)
Week 1	Session 1	Introduction to I-STRONG program	Introduce training equipment; education about muscle strength, fatigue, and pain Level 1 Holding movement
	Session 2	Learning about pain and stress
Week 2	Session 3	Tips for parents: helping teenagers for home and school success
	Session 4	Training your body to relax
Week 3	Session 5	Training your body to relax	Level 2 Creating movement
	Session 6	Training your body to relax
Week 4	Session 7	Getting active without overdoing it
	Session 8	Open session, review progress and adherence to training
Week 5	Session 9	Facing the fear of pain to have more fun	Level 3 Resisting movement
	Session 10	Being a good coach for yourself
Week 6	Session 11	Working through tough thoughts and feelings
	Session 12	How to be heard when talking about pain
Week 7	Session 13	Problem solving	Level 4 Functional movement
	Session 14	Pain action plan
Week 8	Session 15	Review skills and progress
	Session 16	Review pain action plan and problem solving

All sessions required teenager participation. Caregivers were encouraged to attend all sessions, and caregiver attendance was required for sessions 1, 2, 3, 8, 15, and 16. Treatment materials included a trainer manual; a participant manual including educational handouts, skills worksheets, and self-monitoring homework tracking; and audio-video exercise videos to supplement instruction during sessions.

Treatment sessions were co-led by a psychology postdoctoral fellow/pediatric psychologist and an exercise physiologist/physical therapist. Trainers attended a 2-day training to learn how to deliver I-STRONG according to the protocol, with education regarding the unique considerations of SCD pain. The trainer manual was scripted and included structured worksheets and videos to deliver skills and exercise training. Treatment sessions were video-recorded to monitor treatment fidelity. A random selection of 25% of sessions were reviewed by an independent rater using a treatment fidelity checklist. Trainers held weekly meetings with the principle investigator to support treatment fidelity, discuss corrective feedback as needed, and problem-solve any concerns.

Measures

Feasibility was assessed using 4 metrics: (1) study enrollment (percentage of eligible participants that consented), (2) retention rates (percentage of participants who participated through the end of the 8-week treatment period), (3) completion of assessments (percentage of primary, secondary, and exploratory outcome assessments completed), and (4) treatment completion (at least 75% of treatment sessions completed as planned or make-up sessions if missed).

Acceptability was assessed by investigating treatment burden, satisfaction, and tolerability through qualitative analysis of posttreatment individual interviews regarding treatment content (utility, appropriateness), format (convenience, number, and length of sessions), and via adolescent- and caregiver-report on the Treatment Evaluation Inventory, short form. This 9-item questionnaire was adapted to be specific to pediatric SCD and pain. Items are scored on a 5-point Likert scale ranging from 1 (strongly disagree) to 5 (strongly agree). Total scores range from 9 to 45. Scores of ≥27 indicate “moderate” treatment acceptability.³⁹ Participants were also encouraged to share suggested changes for future iterations of I-STRONG.

Safety was assessed throughout the study through careful monitoring and recording of all adverse events (AE) including any significant flares in pain or other symptoms lasting >48 hours or needing medical attention, or any other unanticipated AEs regardless of relatedness to the study. AEs were assessed at each assessment period and through participants’ spontaneous reports during treatment sessions using the Common Terminology Criteria for Adverse Events, version 5.⁴⁰

Primary clinical outcome (Brief Pain Inventory)^41,42 assesses locations of pain (on a body diagram), worst, typical, and least pain intensity, and interference of pain on daily functions over the past week on a numerical rating scale from 0 (no pain/interference) to 10 (severe pain/complete interference). An interference score is calculated by averaging across areas of pain interference. Change in typical pain intensity was the primary outcome of interest.

Patient global impression of change reflects a patient’s belief about the efficacy of the treatment through a single prompt, “Since the start of the study (treatment), my overall pain is…” using a Likert scale ranging from 1 (very much improved) to 7 (very much worse).

Secondary outcomes

Additional core measures recommended by the National Institutes of Health’s Helping to End Addiction Long-term (HEAL) Initiative common data elements assessing anxiety, depression, pain catastrophizing, sleep, and quality of life, as well as supplemental measures of fear of movement were included.

Exploratory outcomes

The following objective assessments were included to evaluate feasibility of completion during each assessment time point. The 6MWT⁴³ is a submaximal test used to assess functional aerobic capacity and endurance by measuring the walking distance covered over a time of 6 minutes. Actigraphy was used to assess physical activity monitoring. Patients were asked to wear a small, hip-mounted actigraphy wearable device⁴⁴ for 7 consecutive days for continuous activity monitoring. Device wearing for any portion of the day for ≥5 days was classified as completion.

Data analysis plan

Total sample size was determined based on meeting a priori feasibility target goals: ≥50% enrollment rate, ≥75% retention rate, ≥90% completion of primary clinical outcome (pain intensity) at 3-month follow-up assessment, ≥75% completion of secondary and exploratory outcomes at 3-month follow-up, and ≥75% of participants completing treatment (ie, completing at least 75% of scheduled treatment sessions).

Acceptability was assessed by counts and percentages to characterize treatment burden, satisfaction, and primary and secondary outcomes. An a priori safety goal was defined as ≤5% of participants with a serious AE (SAE) related to the intervention. The qualitative analytic approach described in phase A was used to identify high-level themes from exit interviews to iteratively optimize I-STRONG.

Due to the focus on optimizing feasibility and acceptability, the pilot trial was not powered to test efficacy. Descriptive statistics evaluated patient-reported global impression of change in pain from before treatment to after treatment, and before treatment to follow-up. A preliminary analysis was conducted only on the primary clinical outcome of pain intensity to evaluate possible change over time using multilevel modeling. Multilevel modeling accounts for repeated measurement within individuals, accommodates for missing data, and includes all available data in analysis. Using a random intercepts model, time was considered a categorical variable, and pretreatment values of typical pain intensity were specified as the reference point. Post hoc analysis calculated the proportion of participants achieving a minimal clinically important difference (MCID) on typical pain intensity (ie, 1-point numerical rating scale reduction) from before treatment to after treatment and to follow-up. Descriptive statistics (means and standard deviations [SD]) are reported for all secondary outcomes and exploratory 6MWT results. Actigraphy data are not presented.

Human subjects review was approved by Western Copernicus Group (WCG) institutional review board. This study was conducted in accordance with the Declaration of Helsinki.

Results

Phase A: intervention modification

In phase A, 39 adolescent and caregiver participants were screened for eligibility, 30 consented to the study (n = 16 adolescents, n = 14 caregivers), of which 63% (n = 12) of teenagers and 70% (n = 12) of caregivers completed qualitative interviews. Nonparticipation was primarily due to nonresponse. There was no significant differential attrition for participation based on demographic characteristics or pain screening risk score.

Participant and CAB feedback regarding intervention modifications were organized into 4 overarching categories: study design considerations, treatment program needs to address unique considerations of chronic SCD pain, identified barriers, and enhancing participant motivation. Table 2 summarizes the feedback across each category and maps onto the modifications and refinements made in collaboration with CAB members to ensure appropriate changes. Feedback was integrated to finalize all study materials, including recruitment materials; study-branded giveaways for engagement; scripted trainer manual; participant binder including educational handouts, skills worksheets, and self-monitoring homework tracking; and audio-video neuromuscular exercise teaching videos to supplement instruction during sessions.

Table 2.

Teenager and caregiver demographics for phase A and phase B

Variables	Phase A: intervention modification	Phase B: feasibility and acceptability
	N (%)	N (%)
Adolescent or young adult	12 (100)	12 (100)
Age, y
Mean (SD)	15.17 (1.53)	16.3 (1.61)
Median (range)	15 (13-17)	17 (13-18)
Sex assigned at birth
Male	6 (50)	7 (58)
Female	6 (50)	5 (42)
Race/ethnicity
Non-Hispanic Black	12 (100)	12 (100)
Education
Grade school	3 (25)	1 (8)
High school or equivalent	9 (75)	11 (92)
Genotype
HbSS or HbSβ0 thalassemia	11 (92)	9 (75)
HbSC or HbSβ+ thalassemia	1 (8)	3 (25)
Chronic pain diagnosis (confirmed via medical chart)	11 (92)	9 (75)
Caregiver	12 (100)	9 (100)
Age, y
Mean	39.4 (6.3)	40.8 (4.4)
Median (range)	38 (33-53)	41 (35-49)
Caregiver relationship
Mother/stepmother	12 (100)	9 (100)
Race/ethnicity
Non-Hispanic Black	11 (92)	8 (89)
Black, ethnicity not reported	1 (8)	1 (11)
Highest education completed
High school or equivalent	6 (50)	3 (33)
Associates or technical degree	3 (25)	5 (56)
College degree	3 (25)	1 (11)
Graduate or higher degree	—	—

Hb, hemoglobin.

Phase B: optimizing feasibility and acceptability through pilot trial

Feasibility

STUDY ENROLLMENT

Medical chart review facilitated initial screening for potential participants (n = 55), and 42% (n = 23) were screened for eligibility, of whom 16 were confirmed eligible. A total of 12 adolescents and young adults (75% who were eligible) and 9 caregivers consented to the study, and 100% initiated study procedures (Figure 1; CONSORT flow diagram). Demographic characteristics for adolescent and caregiver participants are detailed in Table 3.

Figure 1.

Phase B CONSORT diagram.

Table 3.

Adaptations and refinement in response to adolescent, caregiver, and CAB feedback to inform I-STRONG design and content

Adolescent, caregiver, and CAB feedback	Adaptation and refinement
Study design
Enthusiasm for group-based over individual treatment	•All sessions planned as group-based with opportunities for individual problem-solving, modifications, and support during sessions to ensure each participant had an individualized experience as part of the group format
Family-centered as much as possible	•Caregivers required to attend 6 of 16 sessions that were caregiver-focused •Additional interested caregivers and family members encouraged to attend all sessions •Contrasts with many CBT protocols that focus on the teenager and include caregiver for first/last 5-10 min of each session
Experienced trainers knowledgeable of SCD	•Site training involved medial overview of SCD; psychosocial functioning and family dynamics commonly affected by SCD; and training in cultural humility practices for all trainers, coordinators, and research study members before study onset
Virtual vs in-person intervention	•All sessions planned as virtual to maximize reach and minimize barriers to access •Planned time dedicated to developing group dynamics to enhance social connectedness, a perceived benefit of in-person interaction
Treatment program needs
Difference between acute SCD pain, chronic SCD pain, and muscle soreness	•Clarify differences between acute and chronic SCD pain •Include discussion of how to differentiate between pain and muscle soreness •Clarify how treatments and recovery for pain vs soreness differ
Highlight common experiences related to SCD as examples	•Infused examples and language around SCD and common lived experiences of SCD to build group cohesion and normalization
Practical skills for handling stress and communicating pain and treatment needs to others	•Added content on stress and stress management •Added session on evidence-based communication skills training for difficult conversations and self-advocacy
Exercise videos are clearly explained, and need sex, racial, and ethnic representation	•Developed new teaching videos of neuromuscular exercises demonstrated by individuals living with SCD •Exercise teaching videos included a range of representation by biological sex, race, and ethnicity
Physical activity safety and goals	•Reviewed and synthesized the available extant literature on safety of physical activity for individuals living with SCD •Integrated education and tailored goals for engaging in gradual physical activity to optimize safety and chronic pain management
Live testing of neuromuscular exercises by CAB members supported feasibility of execution without difficulty for all but 2 exercises.	•Developed and tested additional modifications to 2 exercises while maintaining fidelity of targeting the muscle and movement
Pacing of treatment session	•Integrated frequent check-ins, breaks, and hydration reminders throughout sessions to support even pace and minimize mental and physical fatigue
Debrief at end of each session for immediate feedback	•Solicited qualitative and quantitative feedback at the end of each session to inform improvements
Consistency across visual handout materials	•All study materials modified and formatted with consistent color scheme, study logo for easy identification, and bulleted text summarizing key points to optimize clarity and understanding •Study binder with all participant handouts provided at the beginning of the intervention to support neurodiverse learning formats
Identified barriers
Scheduling of assessments and intervention sessions	•Minimized requirements for in-person assessment visits (6MWT only) •Scheduled sessions based on days/times that were most convenient for participants (after school/work) •Flexible work schedules for study team members to accommodate for later evening work times
Maintaining interest over time	•Integrated values-based goals to identify personalized goals for each participant •Added time to self-reflect on values-based goal and build motivation to persist and put forth best efforts
Difficult pain days	•Included additional modifications to neuromuscular exercises to allow participation on high pain days •Reinforced values-based goals and encouraged as much participation as possible to minimize all-or-none efforts of participation
Enhancing motivation
Clarifying upfront their reason for participating	•Used patient-centered language to identify common reasons why teenagers might be interested in study participation •Used patient-centered language on recruitment flyers •Participants shared their top 3 reasons for wanting to participate at the time of enrollment
Once they get started, they will feel the benefit	•Expectation management and normalization •Acknowledge some aspects may be different, awkward, silly, or difficult; and with time, practice, and more experience, their feelings about participation may shift •Allows participants “permission” to feel uncertain or uncomfortable, this is normal and expected, and will likely get better as they engage with the group members
Group interaction	•Integrated opportunities for social connection and peer normalization throughout the intervention sessions •Used ice breakers, trivia, and background music based on participants’ preferences
Peer normalization	•Dedicated time for participants to engage with each other about their lived experiences to offer normalization of their shared experiences
Family language on “why” to participate
Add-on to the medicines they are already taking  Designed to help with specific problems related to SCD pain  Group of other teenagers with SCD going through the same thing  Learn new ways to help your body and reduce pain  Get back to doing activities that they miss  Get fit and healthier  Strengthen their muscles	•Common reasons why participants may be interested in engaging in the intervention were shared based on stakeholder feedback •Highlighted throughout the recruitment process •Including a variety of reasons allowed for greater reach of patients who experience a range of ability levels and interest while minimizing stigma associated with nonpharmacological interventions for chronic pain management

RETENTION RATE

One participant was medically withdrawn from the study during the active treatment phase (before attending any sessions), yielding a 92% retention rate in the study.

ASSESSMENT COMPLETION

All participants completed pretreatment assessments. Those who completed the intervention (n = 11 [92%]) also completed posttreatment and 3-month follow-up assessments of primary and secondary outcome measures. Regarding exploratory outcomes, most participants completed the 6MWT and activity monitoring after treatment (n = 10 [83%]) and at 3-month follow-up (n = 9 [75%]).

TREATMENT COMPLETION

Four groups were conducted, and 3 completed the treatment protocol as planned. The second planned group included 3 participants and was prematurely terminated after completing 2 sessions due to low attendance. Specifically, 1 participant initiated new employment that interfered with study participation; and 1 participant was medically withdrawn, thus limiting the group size. Notably, 2 of 3 participants remaining in this group participated in the subsequent group after adjustments to scheduling and had 100% treatment completion in the subsequent group. To ensure adequate group size for subsequent groups, the minimum group size increased from 3 to 4 to account for possible intermittent attendance, and scheduling of sessions was reconfirmed during the baseline assessment.

Across all sessions and completed groups, ≥75% of sessions contained 3 to 6 adolescent participants, treatment completion averaged 95% (range, 81%-100%), and 92% of adolescent participants completed ≥75% sessions as planned or makeup sessions. Most participants who completed the intervention attended a planned or makeup booster session (n = 10 [91%]). Review of recorded session content indicated 97% intervention fidelity to delivery of the manualized treatment.

Acceptability

Overall positive feedback was provided by participants during posttreatment qualitative interviews. All adolescent participants reported overall enjoyment of I-STRONG, that the program felt relevant to their lived experiences of SCD and chronic pain, and indicated perceptions of lessened fear and increased confidence with physical movement, increased participation in daily activities and exercise, and improved energy. Due to the rich content and depth of intervention feedback provided, detailed qualitative analyses will be reported separately to adequately describe participants’ experiences. High-level qualitative feedback as well as key process improvements that informed final modifications for recruitment, retention, and study procedures in preparation for a planned future multicenter randomized controlled trial are detailed in Table 4.

Table 4.

Phase B primary and secondary outcome measures

Outcome	Construct (measure, possible range)	Before treatment, mean (SD)	After treatment, mean (SD)	3-Month follow-up, mean (SD)
Primary	Typical pain intensity (BPI; 0-10)∗	5.75 (2.63)	4.36 (1.96)	3.89 (2.15)
Secondary	Pain interference (BPI; 0-10)∗	3.45 (3.09)	4.24 (2.62)	2.94 (2.15)
	Depressive symptoms (PHQ-8; 0-24)∗	6.50 (5.69)	6.82 (6.52)	5.40 (3.41)
	Anxiety symptoms (GAD-2; 0-6)∗	2.08 (1.72)	1.45 (1.44)	1.20 (1.32)
	Pain catastrophizing (PCS-C; 0-52)∗	24.33 (13.05)	22.82 (14.06)	21.00 (12.33)
	Quality of life (PedsQL; 0-100)∗†	69.03 (15.03)	64.85 (17.25)	73.83 (16.56)
	Sleep quality (ASWS; 28-168)∗†	38.00 (9.73)	37.55 (9.98)	41.00 (6.58)
	Substance use (NM ASSIST‡)∗	0.58 (.90)	0.45 (.93)	0.50 (.71)
	Fear of movement (TSK; 17-68)	25.42 (6.93)	25.82 (7.24)	24.00 (6.78)
	Treatment satisfaction (TEI-SF; 9-45)†	—	34.36 (4.23)	33.30 (3.23)
Exploratory	6MWT†, m	286.18 (94)	314.95 (89.09)	355.03 (78.99)

ASWS, adolescent sleep-wake scale; BPI, brief pain inventory; GAD, general anxiety disorder; NM ASSIST, National Institute on Drug Abuse–Modified; PCS-C, pain catastrophizing scale; PedsQL, pediatric quality of life; PHQ, patient health questionnaire; TEI-SF, treatment evaluation inventory–short form; TSK, Tampa Scale of Kinesiophobia.

^∗Measures required as common data elements for clinical trials funded by the National Institutes of Health’s Helping to End Addiction Long-term (HEAL) Initiative.

^†Higher scores indicative of better functioning on that construct.

^‡Scored based on number of items answered >0; score of >0 indicates substance use.

Participant and caregiver satisfaction of the treatment were relatively high at posttreatment follow-up (adolescent mean, 34.36 [SD, 4.22]; caregiver mean, 37.44 [SD, 4.00]; range, 9-45) and maintained at the 3-month follow-up (adolescent mean, 33.30 [SD, 3.23]; caregiver mean, 35.00 [SD, 3.12]; range, 9-45). Specifically, ≥80% adolescents and ≥85% of caregivers agreed or strongly agreed that the treatment was an acceptable way of dealing with pain and related symptoms, liked the procedures used, believed it was likely to be effective, and had an overall positive reaction to the treatment. In contrast, 50% of adolescents and 67% of caregivers agreed or strongly agreed that they believed the treatment was likely to result in permanent improvement.

No participants experienced a SAE related to the intervention. There were 8 SAEs unrelated to the intervention (eg, hospitalizations related to SCD complications or infection). Reported AEs (n = 18) were of mild severity; included pain, muscle soreness, and fatigue; and were expected, with 38% being possibly or probably related to the intervention. Notably, adolescents and caregivers reported that they did not experience any pain exacerbation related to participating in the intervention. All AEs resolved by study completion.

Preliminary efficacy

Figure 2 suggests most of the adolescent participants reported their global impression of change of pain improved at posttreatment (82%) and 3-month follow-up (90%) assessments, and none reported that pain worsened. Notably, the degree of improvement changed over time, from 45% reporting pain as “much improved” after treatment, to 50% reporting “minimally improved” at 3-month follow-up. Preliminary changes in typical pain intensity indicated an average 1-point reduction in pain from baseline (mean, 5.75 [SD, 2.6]) to after treatment (mean, 4.36 [SD, 1.9]), and maintained at 3-month follow-up (mean, 4.30 [SD, 2.4]; P = .07). Consistent with MCID for pain, 55% of participants achieved MCID change in typical pain intensity at posttreatment assessment, and 67% at 3-month follow-up.⁴⁵ Descriptive statistics of secondary and exploratory outcomes are detailed in Table 5. Although secondary and exploratory outcomes were not evaluated for change over time due to low statistical power, results suggest general patterns of symptom reduction in pain interference, anxiety, depressed mood, and pain catastrophizing, as well as patterns of improved sleep, quality of life, and functional walking capacity.

Figure 2.

Patient-reported global impression of change in pain since the start of treatment (phase B).

Table 5.

Final modifications to I-STRONG content and study procedures based on qualitative feedback and iterative process improvement for planned future randomized controlled trial

Adolescent, caregiver, and CAB feedback, and lessons learned	Modifications, refinements, and solutions
Study design
Refinement of eligibility criteria	•Added exclusion criterion of comorbid medical conditions with significant gait or musculoskeletal limitations (eg, cerebral palsy) that would preclude participant engagement
Inclusion of clinically meaningful patient-reported outcomes •Participants consistently shared meaningful changes in energy/fatigue, confidence in movement, pain acceptance, and group cohesiveness	•Include validated patient-reported outcome measures assessing these constructs in future trials
Intervention protocol
Neuromuscular exercise modifications •Two neuromuscular exercises were consistently identified as most challenging for participants	•Included additional modifications for these specific exercises to ensure individualization based on range of movement ability
Session attendance during participant hospitalization •Participants eager to engage in sessions even during hospitalizations	•Included seated and supine modifications for all exercises to ensure engagement across a range of movement ability
Session homework practice and plans •Patients expressed homework practice varied based on competing demands	•Reorganized homework practice plans and handouts to improve organization, specificity, and facilitate integration into daily routine
Recruitment strategies
Delayed enrollment •Time lag between initial contact with family and recontact for consenting	•Use of text messaging to caregiver sooner rather than call or email only •Planned recruitment during school breaks in which families can be contacted more easily and inquired about future availability
Contacting families •Patients no show clinic visits, calls/texts/emails go unanswered	•Generated a QR code of recruitment infographic that was texted to family to facilitate ease and timely contact
Retention strategies
Scheduling group start time •Families need later start time to accommodate school and work schedules; trainers had personal time conflicts after traditional work hours	•Expanded the number of trainers available who can work later hours •Developed a system of cross coverage for intermittent out of office for trainers
Family availability •Patient/family interested but after school hours interfere with extracurricular activities	•Maintained a list of patient/families who are interested for a future group that may be scheduled during the summer or off-season
Research staff turnover	•Trained backup research staff alongside primary staff •Established communication system and touchpoints with patients and families on study activities •Video recorded study staff trainings for ease and efficiency of retraining and onboarding

QR, quick response.

Discussion

I-STRONG for SCD is an innovative, multicomponent, integrative behavioral intervention designed specifically for youth with chronic SCD pain, incorporating feedback from a CAB to modify an existing evidence-based CBT and neuromuscular exercise training for pediatric chronic pain. This mixed-methods, multiphase study provides evidence for the feasibility, acceptability, and preliminary efficacy of a novel intervention to reduce pain among adolescents with SCD. The high levels of treatment completion, low dropout rate, strong treatment satisfaction, and minimal safety concerns underscore the importance and value of community-engaged approaches to treatment development and design among underserved populations who experience pain, especially in the setting of marginalization and health disparities.²⁵

Partnership with a CAB, adolescents and young adults with lived experience of chronic SCD pain, and their caregivers, and multidisciplinary medical experts were integral to the iterative process of informing modifications and refinement of the I-STRONG protocol to the chronic SCD pain experience. Modifications spanned enhancing treatment content to better match SCD lived experiences, exercise modifications to address common SCD concerns, and addressed barriers such as scheduling and engagement. Site-based research teams remained in close contact with families throughout the study to foster trust and open communication, prioritized flexibility in scheduling to accommodate after school responsibilities or transportation concerns, and encouraged extended family member attendance and involvement and physical engagement to maximize opportunities to participate. As a result, the I-STRONG pilot findings indicated high feasibility and acceptability as demonstrated by >90% attendance and treatment completion rates, >90% assessment completion, and consistently positive postintervention qualitative feedback, highlighting treatment satisfaction, improvements in energy, and confidence with physical movement. Preliminary efficacy was supported by >80% patient-reported global improvement in pain after treatment and at follow-up, and >55% participants reported minimal clinically important pain reductions. Clinically important reductions in pain and maintenance of treatment-related pain reductions will be further tested in a well-powered randomized controlled trial. Overall, these results add to the small body of literature that finds treatments designed to meet population-specific needs, whether by age, disease population, or referring concern, may be more effective in improving health outcomes compared with treatments that are not personalized to their disease-specific needs.^46,47

Study results build on the growing body of work demonstrating that multicomponent interventions, such as combined CBT and neuromuscular exercise training, are more effective than CBT alone for chronic pain management²² and offer a unique, synergistic approach to SCD pain. In fact, adolescents with chronic SCD pain expressed desire to engage in more physical activity, yet struggled with underlying fear, worry, and pain as primary barriers,²³ priming them to benefit from an approach that combines coping skills training with progressive exercise training under careful supervision. The group-based treatment format also offered opportunities for social connection, accountability, and enhanced motivation.²³

Although the pilot trial was small, strengths of the study include a systematic and iterative approach to modifications; partnership with persons living with, and managing, chronic SCD pain to inform development and design; and integration of qualitative and quantitative data. Our rigorous approach to modification allowed retaining fidelity to evidence-based treatment components while optimizing design, content, engagement, and minimizing barriers. Telehealth delivery with live trainers will facilitate dissemination even with a limited workforce of psychologists and physical therapists with expertise in SCD.

Yet, our results should be interpreted in the context of limitations that restrict generalizability. Due to the focus on modification, feasibility, and acceptability, the small sample size was neither intended to provide the statistical power to detect changes in the outcome measures nor was a control group included. Use of the pediatric pain screening tool to identify those who may be at risk for poor pain-related outcomes indicative of recurrent and chronic pain may have contributed to broader eligibility criteria and inclusion of patients experiencing recurrent pain with low pain intensity. Next steps include a future, well-powered and rigorously designed multicenter randomized controlled trial of I-STRONG to evaluate efficacy on the reduction of chronic pain and improved functioning. Future outcome measures should extend beyond pain and function to include the biopsychosocial factors that may exacerbate or maintain pain in addition to objective measures of physical activity to assess increased engagement. Additionally, a longer-term follow-up would evaluate whether treatment gains are maintained over time and inform opportunities for broad dissemination and clinical implementation.

Conflict-of-interest disclosure: The institutions with which S.S., J.T.M., L.E.C., T.K., and S.K.-Z. are affiliated receive past, current, and ongoing grant funding from National Institutes of Health, including the National Heart, Lung, and Blood Institute, National Center for Complementary and Integrative Health, National Institute of Neurological Disorders and Stroke, National Institute of Nursing Research, National Institute of Child Health and Human Development, and National Institute of Arthritis and Musculoskeletal and Skin Diseases (grants R03HL164333, R61AT012421, K12NS130673, R01NR020781, M01RR008084, R21HD116484, R01AR070474, T32AR069512, P30AR076316). The institution with which G.D.M. is affiliated receives past, current, and ongoing grant funding from the National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases (grants U01AR067997, R01AR070474, R01AR055563, R01AR076153, R01AR077248, and R61AT012421), the Department of Defense (grant W81XWH22C0062), Department of Veteran’s Affairs (CReATE [cartilage regeneration using advanced technologies to enable motion] Motion Center), and the Arthritis Foundation Osteoarthritis Clinical Trial Network. G.D.M. consults with commercial entities to support commercialization strategies but has no direct financial interest in commercialization of the products; has received industry-sponsored research funding (to his institutions) related to injury prevention and sport performance and has current ongoing funding from Arthrex Inc to evaluate anterior cruciate ligament (ACL) surgical treatment optimization strategies; receives author royalties from Human Kinetics and Wolters Kluwer; and is an inventor of biofeedback technologies (patent US11350854B2, Augmented and Virtual Reality for Sport Performance and Injury Prevention Application, approved 6/7/2022, software copyrighted) designed to enhance rehabilitation and prevent injuries, which receives licensing royalties. The remaining authors declare no competing financial interests.