Sickle cell disease (SCD) is an orphan disease with multifactorial impact. In the United States, the incident rate of SCD has remained constant [1]. However, SCD is projected to increase from 304,800 newborns annually to 404,200 newborns by 2050 worldwide [2]. SCD is the most common inherited blood disorder in the United States [3], with annual health care cost of US $2.4 billion [4] for 100,000 diagnosed Americans. Current human diasporas and massive migration from Africa, Middle East, Mediterranean region, Central and South America, and India contribute to the sickle cell gene pool in the United States, as does a growing Hispanic population [2]. People living with SCD were once destined for recurrent morbidity or early death, but now, live into their forties and beyond [5]. In the United States, for people with HbSS, HbSβ⁰, or HbSD, the median age of survival is 48 (95% CI 44.4-58.4) years and for people with HbSC or HbSβ⁺, the median age of survival is 54.7 (95% CI 38.6-62.9) years [6]. People living with SCD have lifelong recurrent episodes of acute pain and substantial persistent pain together with other symptoms including respiratory threats, organ failure, stroke risk, and stress and disruption in their lives and those of their family [7-15]. Evidence indicates that patients with SCD who survive beyond childhood continue to live most days with persistent pain that can affect any organ owing to ischemia [13].

The chronic pain associated with SCD is often rated as more intense than childbirth pain and persists for years [16]. Recurrent, unpredictable, and disabling episodes of vaso-occlusive pain was the primary reason for >100,000 annual SCD emergency department (ED) encounters and hospitalizations [17]. People with SCD have an average of 2.59 (95% CI 2.53-2.65) ED visits or hospitalizations per year [17]. ED visit and hospitalization rates are 2 to 6 and 7 to 30 times higher, respectively, among African American individuals with SCD visits than those without SCD [18].

Other studies report strong positive relationship between the frequency and severity of pain and death [13,19-22]. Currently, the only cure for SCD is allogeneic hematopoietic stem cell transplantation, with limited availability owing to the risk of transplantation-related mortality [23]. Potential cures for SCD include transferring the causal β-globin gene, editing sickle β-globin mutation, or reactivating fetal hemoglobin, the research for which is still ongoing [24]. As stem cell transplantation is not without considerable risk, it is usually reserved for patients with severe symptoms of SCD [25]. Given the strong association between severe SCD pain and death [13], there is an urgent need to find readily available therapies for controlling SCD pain.

Stress, associated with pain in patients with SCD, is correlated with overactivation of the hypothalamic-pituitary-adrenal axis hormones or neurotransmitters (eg, cortisol, norepinephrine, and epinephrine), which trigger the fight-or-flight responses and intensify responses to nociceptive pain (somatic and visceral tissue damage) [26-28]. Stress can also activate neuropathic pain mechanisms (neural tissue damage) implicated as part of SCD pain [16]. In patients with pain, the perception of stress can lead to stress-induced hyperalgesia (increased pain from a painful stimulus) [29]. Findings from studies of patients with SCD [30,31] and other pain conditions [32] show small to medium positive associations between stress and pain. In a pilot study of 52 adult patients with SCD, we found that compared with patients who perceived low psychological stressors from their physicians, those who perceived high stressors from their physicians also reported greater stress (P<.001) and pain (P=.002) [30]. Results were similar for psychological stressors from nurses (perceived stress: P<.001 and pain: P=.02) [30]. Others found that patients with SCD who reported high stress also reported high average pain [31], and increased stress intensity was associated with increased same-day pain in patients with SCD [33]. Cumulative findings from these studies provide strong evidence of the association of stress with pain in patients with SCD. The hypothalamic-pituitary-adrenal axis theory posits that stress reduction interventions have the potential to reduce SCD pain.

The use of pain self-management in SCD has gained much attention in recent years. Pain self-management techniques can include deep breathing exercises, progressive relaxation, and guided imagery [34]. Patients with SCD are ideally suited for nondrug therapies. In a recent study of 227 patients with SCD, approximately 92% reported using nondrug therapy in the previous 6 months to manage pain [35]. Studies of nondrug therapies in patients with SCD found reduced perceived pain intensity [36] and reduced clinical pain [37,38]. Guided relaxation, which is one of many tools used in cognitive behavioral therapy, is designed to help patients identify triggers for pain, modify problematic emotions or behaviors, and develop coping skills [39]. By using relaxation and stress management to guide patients away from negative feelings and behaviors, we can weaken the inclination to use opioids as the only method of pain management and strengthen their repertoire of strategies with alternative healthy actions, thereby improving their day-to-day relationship with pain.

The use of opioids as the mainstay of therapy for both acute and persistent SCD is not ideal. Opioid analgesics are known to cause severe side effects, including death from overdose. They are frequently prescribed for SCD pain; however, accumulating evidence suggests the need to incorporate nondrug therapies as strategies for managing SCD pain systematically [40]. A recent study characterized opioid analgesic use in patients with SCD and showed that 40% of them were prescribed opioids in the previous 12 months [41]. Furthermore, 3% of pediatric patients and 23% of adult patients used high doses (>30 mg of oral morphine equivalence [OME] daily) [41]. Findings also suggest that patients with vaso‐occlusive pain crisis (acute) and avascular necrosis (chronic) reported using high-dose opioid use [41].

Patients who use high opioid doses were more likely to use nonsteroidal anti‐inflammatory drugs, visit acute health care facilities, and indicate that they experienced pain on most days [42]. The opioid epidemic in the United States stems from heavy reliance on opioid therapy for controlling all pain types, including persistent pain, a practice against the Center for Disease Control recommendation that nondrug therapies are preferable for treating chronic pain [43]. Compared with the national average, patients with SCD have lower opioid addiction rates and fewer deaths from overdose [44]. Between 1993 and 2013, a total of 174,959 individuals in the United States died from opioid prescription overdose. During the same period, 95 patients with SCD died from opioid prescription overdose [44]. To mitigate the risk of death from opioid overdose and other side effects of opioids in patients with SCD, behavior change strategies are sorely needed, which will empower patients to embrace self-management principles, including the systematic use of nondrug therapies as complements to opioids.

Providing behavior change strategies via mobile health (mHealth) apps or internet-delivered interventions aligns with the Federal Pain Research Strategy to promote and enable pain self-management [45]. In a previous study, Ezenwa et al [37] found that an internet-enabled, stand-alone distraction and relaxation intervention demonstrated the feasibility and acceptability of the intervention in adult outpatients with SCD. As in this previous study [37], the design for this study is based on a multidimensional theory of pain supported by decades of research [46]. Operating within this theoretical framework, participants with SCD will continue taking opioid analgesics during the study period. A well-designed study, such as ours, will provide a behavior strategy with the potential of reducing opioid use.

The focus of this study is to evaluate the effectiveness of a self-management intervention that promotes the use of relaxation and distraction exercises (RDEs) in reducing pain, stress, and opioid dependency among adult outpatients with SCD. Specifically, the aims of this study are the following:

The study is a randomized controlled trial (RCT) of the short-term (8 weeks) and long-term (6 months) effects of YCWS on efficacy outcomes (pain, stress, and opioid use), designed to determine the short-term and long-term effects of the YCWS intervention and to evaluate models that predict patient outcomes based on their group assignment and their personal and environmental characteristics.

We are recruiting patients both in person and internet-based throughout the state of Florida, including the University of Florida (UF) Health-Shands in Gainesville and UF Health-Shands in Jacksonville. Thus, data collection and intervention delivery occur throughout Florida, with UF Health-Shands in Gainesville as the primary site for data collection, intervention delivery, and data analysis.

The UF institutional review board (IRB) is the approving IRB of record and has approved all the recruitment and study procedures (IRB202000984).

We will recruit from the UF Health-Gainesville and UF Health-Jacksonville hematology clinics and the UF Health-Jacksonville transition program. The UF Health-Shands Hospital, Gainesville, adult sickle cell program has a clinic panel of 497 adult patients with SCD. Of the 497 patients, (283/497, 57%) are women and (452/497, 91%) are African American individuals. The adult SCD program consists of a multidisciplinary team including 5 medical hematologists, 2 advanced registered nurse practitioners, 1 physician assistant, and 1 registered nurse. The UF Health-Jacksonville adult sickle cell program has a clinic panel of 569 adult patients with SCD. Of the 569 patients, 318 (56%) are women and 540 (95%) are African American individuals. The UF Health-Jacksonville adult SCD program consists of a multidisciplinary team including 1 medical hematologist and 1 advanced registered nurse practitioner.

The study is registered on ClinicalTrials.gov. We will use web-based recruitment processes, including posting recruitment information on the UF study Facebook page and various internet listservs to identify and recruit adults with SCD from across Florida. We will also use colorful posters, flyers, and brochures developed for this study and distribute them in sickle cell clinics and health fairs and through university bulletin boards. In addition, we will work directly with sickle cell organizations, community-based organizations, health care networks, and churches to post recruitment flyers aimed at encouraging adults to participate in and advertise the study within their networks throughout Florida.

For those who meet the eligibility criteria, we anticipate enrolling 195 participants to retain 170 (87.2%) participants with complete data at 8 weeks, based on a 13% attrition rate observed in our previous longitudinal studies in which follow-up was more than a year. We will strive for a sample in which 95% participants have African descent and approximately 50% are women. Our team has been exceptionally successful in conducting longitudinal studies using tablet technology with this vulnerable population and recruiting and retaining patients with SCD for pain research [16,47-50].

This is an internet-based study, with all screening and consent processes completed by the research specialist (RS) or the community health worker either in person, internet-based, through email, or through US postal service, depending on the patient’s needs. The RS or community health worker will explain the study to the patients and ascertain their willingness to participate. Patients will be informed that their participation is voluntary and that a decision to decline participation will not affect their care. Patients who choose to participate will be asked to sign a written consent form. We will use one of the following methods: (1) patient will sign the consent form in person and will be given a copy, which they may keep for their record; (2) we will email the consent form for the patient to sign and email back to the RS; or (3) we will send 2 copies of the consent form with a self-addressed envelope with paid postage to the patient using the address provided. The patient will sign the consent form, keep a copy for their record, and mail a copy back to us. Patients recruited via phone or email will sign the written consent form on the day of their first study visit, if occurring in person. Otherwise, patients will sign the consent form electronically or via the other consenting methods described previously. The RS who will assist individuals in these screening and consent processes will be trained in good clinical practices for research and IRB and Health Insurance Portability and Accountability Act procedures. The training includes role-playing with the principal investigator (PI) and retraining if the staff deviate from the proper processes.

We will use permuted block randomization with stratification based on worst pain intensity (≤5 or >5) to assign the 195 consecutively selected patients to the 2 study groups. The assignment will be blind until a sealed electronic envelope is opened after the patient completes the pretest data collection procedures.

An important retention strategy is to engage the patients as active partners in the study by explaining the importance of their contribution. We have built trusting relationships with the clinic staff and patient panel, which facilitated the success of our feasibility study and an 18-month longitudinal study (1R01HL124945) that have resulted in several publications [50-55]. Other important retention and adherence strategies include contacting participants for data collection and updating contact information every month. We hired a health care worker from the community to serve as the study support staff for the YCWS intervention. We will send electronic birthday cards and birthday wishes via email and text message. We will also obtain participants’ addresses, telephone numbers, and 3 other secondary contacts to track them during the 6-month study. We will provide incentives to motivate individuals to enroll in the study, maintain interest, and sustain participation for 6 months of self-monitoring or YCWS. All participants will retain the US $150 Galaxy tablet they use for the study as acknowledgment of their time and participation. We will pay US $50 per month as internet access costs for each participant for 6 months. At the end of 6 months, the total incentive is US $450 per participant, which includes the study tablet and accessory cost. In addition, we will use other general study procedures, including (1) text messaging, video messaging, emailing, or calling participants to remind them if they have not provided data for the day and to encourage them to do so and (2) updating patient addresses and phone numbers as needed during each contact.

The PI will conduct reliability assessments for the RS’s implementation of the protocol on a random sample of 20% of the study measures. Although this assessment cannot be blinded, the RS will not be informed of the reliability check until the baseline data collection procedure is underway. If there are any deviations from the protocol, the RS will undergo additional training and supervised data collection to ensure protocol adherence.

To improve fidelity, we will ensure that participants use the YCWS intervention as intended by monitoring the participants’ YCWS system use on the web. During the first 8 weeks, we will call or text participants 2 hours before the next data collection time if the patient does not enter data after 24 hours of system-generated alerts or reminders and has missed the period they indicated for completing the study, to encourage the use of YCWS. We will also ascertain if they are having trouble with accessing the program and will troubleshoot with the participants to resolve any issues. We will also monitor the participants’ self-monitoring of stress, pain, and opioid use in both groups. As a measure of intervention fidelity, the use of the system and measures will be documented by the app software that automatically writes time-stamped data to a SQL database. The fidelity of our pilot feasibility protocol is rigorous as the program is computerized and consistently implemented. In addition, we will monitor mobile device use, and time of use will be documented in the database to determine the intervention dose.

The research data will be collected electronically using laptop and pen tablet computers. All the study surveys may be completed via the web using an app developed for this study. This application will contain PAINReportIt, a computer program developed by DJW to collect participants’ pain information and other surveys in electronic format. Participants’ data will be written directly to that server and will not reside, even temporarily, on the laptop or pen tablet computer. We will use HTTPS for encrypted data transfer to the College of Nursing server. The data will be stored in a secure College of Nursing server with access restricted to the immediate study personnel. All patients will be assigned a code number, and the research team will identify their data only with that code number. The link of the code numbers to the participant identifiers will be kept separate from the study data. Only the investigators and key personnel will have access to the code or master key. Any hard data collected will be stored in a locked office at the College of Nursing.

The software design will make every effort to reduce user errors; all data will be entered directly by the participant using an interface tested with cognitive interview methods that informed the final interface design. Consistency checks are built into the software so that inconsistent data (eg, out of range or logically inconsistent) are flagged immediately to inform the users and assess their intent. In addition, there will be more comprehensive consistency checks before data analysis. Inconsistent data points will be treated as missing. On the basis of our previous studies with this web application, we expect the percentage of inconsistent data values to be very low (<0.5%).

As technology advances, the use of mHealth apps is becoming an integral part of daily life, including for self-management of chronic conditions. Web-based interventions and technologies are reported to have high usability and acceptability as a tool to monitor and self-report daily pain [73-75], monitor medication adherence [76-79], increase SCD reproductive knowledge scores [80,81], and reduce current pain and stress levels [37]. To the best of our knowledge, we are the first to use an mHealth intervention with self-management RDEs to reduce stress and improve SCD pain control, with a concomitant reduction in opioid use.

This protocol paper presents the design of the RADIANCE study, an RCT with the long-term goal to reduce stress and improve pain control in patients with SCD with less opioid use. The intervention with self-management RDEs, YCWS, can offer interactive learning that allows sustained or repeated sessions. Although the intervention may have no direct benefit to individual participants, it may provide individuals with previously unrecognized insights about their stress, pain, and opioid use and options for self-management of these symptoms.

A strength of this guided relaxation study is its web-based design and implementation that provides patients with the ability to interact with the program at their convenience in real-world settings. By providing the tools to reduce their pain, it may help patients with SCD to feel empowered. Given that the guided relaxation is web-based, the patients may have a sense of control and empowerment. However, the web-based design can also be a limitation if internet connection becomes an issue. We attempt to mitigate this potential effect by making the intervention platform independent and allowing patients to go to the library and use the library computer or use their other smart devices for the study. Furthermore, the findings of this study will be generalized only to the state of Florida and not nationwide.

Although recruiting patients from health care networks and churches is a new strategy for us in Gainesville, Florida, this will likely be an opportunity for access to affected communities (ie, college students and other young adults). We will report on the patients’ YCWS web-based activities, data on system use, and pain and stress intensity. The study has the potential for assisting people to develop the confidence necessary to self-manage stress that could intensify their acute or persistent SCD pain. If demonstrated to be effective, this internet-based and web-based intervention could be made available nationwide and, eventually, worldwide.

To maximize the dissemination of this study, we will share methodological approaches, data, and results generated from this study by publishing our findings in research journals that are indexed by PubMed and generally accessible to the research community. We will also present the findings and methodologies at national and international research and health care conferences in accordance with the proposed study time line.