Buprenorphine for the Management of Pain in Children With Sickle Cell Disease

Background and Rationale

Sickle cell disease (SCD) is an inherited red blood cell disorder that affects more than 100,000 people in the United States and millions worldwide. Recurrent episodes of severe pain, called vaso-occlusive crises (VOC), are the most common reason children and young adults with SCD are hospitalized. These pain episodes are typically treated with opioid pain medicines, most often delivered through a patient-controlled analgesia (PCA) pump that provides a continuous background dose along with patient-activated bolus doses. Full agonist opiods such as hydromorphone and morphine, together with the long-acting and short acting oral opioids often started later in a hospital stay, are effective but carry risks of tolerance (needing more medicine over time for the same effect) and opioid-induced hyperalgesia (a state in which opioids paradoxically increase pain sensitivity), both of which may contribute to the chronic pain that many people with SCD experience over time.

Buprenorphine is an opioid medicine that behaves differently from full agonists: it is a partial mu-opioid receptor agonist and a kappa-opioid receptor antagonist. It has been used since 1981 to treat pain and has also been used to treat opioid use disorder. In prior studies of adults with SCD, using buprenorphine for chronic pain has been associated with lower daily opioid doses and fewer hospital and emergency department visits. Buprenorphine also appears to have a "ceiling effect" for respiratory depression, meaning its effect on breathing plateaus at higher doses, unlike full opioid agonists. However, no prior study has examined whether buprenorphine can be used safely for an acute sickle cell pain crisis in place of the long-acting oral opioid a hospitalized patient would otherwise receive, and there is no established safe, tolerable dose of buccal (dissolved between the cheek and gum) buprenorphine (BELBUCA) in this age group. This study is designed to address both questions. Buprenorphine is approved in the intravenous (IV) formulation for pain in children, but this study represents an effort to understand a specific use and specific delivery mechanism (buccal dissolving film) of this medication.

Study Design and Overview

This is a Phase 1, single-dose, open-label, single-institution, dose-escalation safety study of buccal buprenorphine (BELBUCA) in adolescents and young adults with SCD hospitalized for an acute pain crisis. All participants receive the same study drug; there is no placebo group and no randomization. Instead, the study uses a Bayesian Optimal Interval (BOIN) design, a statistical dose-finding method, to identify the highest dose that can be given safely.

To preserve the hospital's usual approach to treating a sickle cell pain crisis while still isolating the effect of the study drug, each participant's hospitalization is organized into three phases:

Phase 1 (Acute stabilization / standard of care): After initial treatment in the Emergency Department, participants are started on standard-of-care pain management, including a demand-and-continuous (basal) hydromorphone PCA, non-opioid adjuvant medicines (such as acetaminophen, ketamine, and NSAIDs), IV fluids, and non-drug comfort measures such as heat packs. Continuous monitoring of breathing, oxygen level, and carbon dioxide level begins during this phase. No study drug is given in Phase 1.

Phase 2 (Stabilization and introduction of the oral pain regimen): When a participant meets pre-specified "readiness" criteria indicating they would, under usual hospital practice, be ready to transition from the PCA to a long-acting oral opioid, the continuous (basal) portion of the PCA is discontinued. After a minimum one-hour equilibration period, during which the participant continues to have access to demand-only PCA dosing, the participant receives a single dose of buccal buprenorphine in place of the long-acting oral opioid that would otherwise have been started. Dosing occurs within a standardized morning-to-early-afternoon window (8:00 AM-3:00 PM) to reduce variability related to time of day. The dose given (75, 150, 300, or 450 micrograms) depends on the dose-escalation cohort to which the participant is assigned.

The readiness criteria that must all be met before a participant enters Phase 2 and receives study drug are:

• Stable or decreasing pain scores (Numeric Rating Scale) for 8 consecutive hours;
• Stable or declining demand-PCA use over the preceding 8 hours; or
• Agreement by the inpatient Pain Service and Hematology team that the participant would, under standard care, be ready to move from PCA to a long-acting oral opioid; and
• No physiologic or clinical findings meeting Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 Grade 3 or higher.

Phase 3 (Transition off study drug): After the post-dose monitoring and assessment period, the care team and participant jointly decide whether to resume a basal PCA infusion, start a long-acting full agonist oral opioid, continue demand-only PCA or transition to short acting full agonist opioids for the remainder of the hospitalization. Because both buccal buprenorphine and the institution's standard long-acting oral opioid (extended-release morphine) are dosed twice daily, participants could transition to a full-agonist long-acting opioid as early as 12 hours after the study dose if clinically appropriate.

By separating the decision of when to give the study drug (the Phase 2 readiness criteria) from what PCA structure is running at the time of dosing (basal infusion stopped, demand-only continued through dosing), the design allows the pre-dose and post-dose 8-hour opioid-use windows to be measured under identical demand-only PCA conditions. This ensures that any reduction in opioid use observed after buprenorphine administration can be attributed to the study drug itself, rather than to a simultaneous change in how the PCA was configured.

Dose-Escalation (BOIN) Design

The study uses a Bayesian Optimal Interval (BOIN) design to identify the maximum tolerated dose (MTD) of buccal buprenorphine, targeting a dose-limiting toxicity (DLT) rate of 0.25 (25%). A DLT is defined as any of the following occurring within the 48-hour observation window after the study dose and judged by the study team to be at least possibly related to the study drug:

• Any primary safety-endpoint event (described below), including transfer to a higher level of care such as the ICU, acute chest syndrome, stroke, or severe mental status change; severe somnolence or disorientation; severe low oxygen (hypoxemia); or severe low breathing rate or elevated carbon dioxide (hypoventilation);
• Administration of naloxone (an opioid-reversal medicine) for sedation or breathing problems;
• Any CTCAE v5.0 Grade 3 or higher adverse event attributed to the study drug.

Dosing begins with the lowest planned dose level (75 micrograms) in a cohort of 5 participants. Based on the number of DLTs observed at a given dose, pre-specified BOIN decision rules determine the next step:

With 5 participants evaluated at a dose: 0 DLTs leads to escalation to the next higher dose; 1 DLT leads to expanding that dose cohort to 10 participants; 2 or more DLTs leads to de-escalating to the next lower dose; 3 or more DLTs leads to eliminating that dose and all higher doses from further use.

With 10 participants evaluated at a dose: 0-1 DLTs allows continuation/expansion at that dose; 2 DLTs means the dose stays at its current level without further expansion; 3 or more DLTs leads to de-escalation; 5 or more DLTs leads to elimination of that dose and all higher doses.

Planned dose levels are 75, 150, 300, and 450 micrograms. The study is considered complete once the highest dose found to be safe has been expanded to a full cohort of 10 participants, for an anticipated total of approximately 25 participants (four cohorts of 5, with the final tolerated dose cohort expanded to 10). The trial is stopped early for safety if the lowest dose (75 micrograms) itself meets the dose-elimination boundary, or if any of the pre-specified stopping rules described are met.

Because the peak plasma concentration of buprenorphine, and the associated risk of respiratory depression, typically occur approximately 3 hours after dosing, the 48-hour monitoring window used to define a DLT captures the period of highest risk, even though it is shorter than buprenorphine's full elimination half-life. Participants continue to have structured monitoring through hospital discharge, followed by a 30-day safety follow-up.

Study Population

Eligible participants are 12 to 22 years of age with a confirmed diagnosis of SCD (any genotype) who present with an acute sickle cell pain crisis, weigh more than 50 kg, and, for those of childbearing potential, have a negative pregnancy test during the index admission. Participants are excluded if they have a hypersensitivity or allergy to buprenorphine; cannot provide informed consent or assent; have significant respiratory depression; have gastrointestinal obstruction, including paralytic ileus; have a history of seizures; have shock physiology; have severe hepatic impairment; are using certain sedating medicines newly initiated during the admission; are using strong CYP3A4 inhibitors or inducers; are currently using, or recently used, monoamine oxidase inhibitors (MAOIs); or are actively breastfeeding. Because this is a hospital-based study, eligible patients are approached when possible before or at the time of presentation to the Emergency Department, and re-confirm their assent/consent if the decision is made to admit them.

Concomitant Medication and Drug-Interaction Management

The prescribing information for buccal buprenorphine (BELBUCA) lists several categories of drugs that may interact with buprenorphine. The protocol distinguishes drug classes that are exclusionary (participants using these cannot enroll) from those that are permitted with additional monitoring:

Excluded from the study: monoamine oxidase inhibitors (MAOIs); mixed agonist/antagonist or partial-agonist opioids (such as butorphanol and pentazocine); and strong CYP3A4 inhibitors or inducers.

Permitted with enhanced monitoring rather than excluded: benzodiazepines and other CNS depressants that are chronic, stable outpatient medicines (new initiation of these during the monitoring window is not permitted); serotonergic drugs, including SSRIs, SNRIs, tricyclic antidepressants, triptans, and 5-HT3 antiemetics such as ondansetron; skeletal muscle relaxants; diuretics; anticholinergic drugs; and antiretroviral medicines.

Because serotonergic medicines are common in this population and are permitted rather than excluded, the study team performs structured surveillance for serotonin syndrome, a drug interaction that can cause mental status changes, autonomic instability, and neuromuscular findings such as clonus or hyperreflexia, at each scheduled safety assessment.

Primary and Secondary Outcomes

The primary (safety) endpoint is defined as the absence, after the study dose, of each of the following: transfer to a higher level of care (such as the ICU), acute chest syndrome, stroke, or another acute life-threatening event; severe somnolence, based on a standardized sedation score, or disorientation that persists despite efforts to arouse the participant; severe low oxygen saturation despite supplemental oxygen; severe slowing of breathing or elevation of carbon dioxide levels; administration of naloxone for sedation or breathing problems; or any CTCAE v5.0 Grade 3 or higher adverse event attributed to the study drug.

Secondary endpoints include: the change in pain scores in the 8 hours after the buprenorphine dose compared with a pre-dose baseline and a later post-transition period; the change in cumulative full-agonist opioid (PCA) consumption, converted to weight-scaled intravenous morphine equivalents, over the same before/after windows; patient and parent satisfaction with pain management, assessed by survey together with pain, sedation, and side-effect data; and preliminary pharmacokinetic data describing how buprenorphine is absorbed, distributed, and cleared in this age group.

Study Procedures and Monitoring

Throughout the study, participants have continuous cardiorespiratory monitoring, including continuous pulse oximetry and continuous non-invasive carbon dioxide monitoring using nasal end-tidal CO2 and/or transcutaneous CO2 devices, which are checked and calibrated by hospital biomedical engineering staff before use. Monitors are set to alarm at a CO2 level of 65 mmHg or higher, which triggers a standardized bedside assessment and escalating response protocol, including efforts to arouse the participant and encourage deep breathing, temporary suspension of PCA button access, and administration of naloxone if the participant cannot be aroused.

Pain scores (Numeric Rating Scale) and Modified Ramsay Sedation Scores are collected every 4 hours, along with vital signs. Safety assessments occur at least every 12 hours. Concomitant medications, sickle cell genotype, demographic information, and other clinical data are recorded from the electronic health record and entered into a secure, HIPAA-compliant REDCap database.

Pharmacokinetic blood samples are collected opportunistically, meaning only when blood is already being drawn for clinically indicated laboratory tests, so no additional needle sticks are performed solely for research purposes. The exact timing of each sample relative to the study dose is recorded for use in population pharmacokinetic modeling.

Approximately 48 hours after the study dose, participants and involved care team members are sent a link to a brief REDCap satisfaction survey, to be completed by the time of hospital discharge. A structured 30-day (plus or minus 5 days) safety follow-up is conducted for every enrolled participant, consisting of a telephone or telehealth contact and a review of the participant's electronic health record for any interval hospital or emergency department encounters or complications that could be related to the study drug.

Withdrawal, Safety Oversight, and Reporting

Participants can be withdrawn from further study procedures at any time, at the request of the participant or parent, or at the discretion of the clinical team, particularly if a primary safety-endpoint event occurs, a CTCAE v5.0 Grade 3 or higher adverse event attributed to study drug occurs, consent or assent is withdrawn, or a new pregnancy is identified. Participants, or for minors their parent or guardian, may withdraw consent at any time, and a minor's withdrawal of assent is honored even if a parent disagrees.

An independent four-person Data Safety and Monitoring Board (DSMB), composed of an ICU physician, a hospitalist physician, a hospital nurse, and a statistician, reviews study data at least every 6 months. The DSMB also convenes if 2 dose-limiting toxicities occur within 48 hours of a dose, if more than 2 participants in a cohort ask to be withdrawn, if a study-drug-related death occurs, or if 2 or more study-drug-related Grade 3 or higher adverse events of the same type occur, which also triggers a temporary pause in enrollment pending DSMB review. Serious, unexpected adverse events reasonably related to the study drug are reported to the FDA within standard federal timelines, and events meeting institutional criteria are reported to the Boston Children's Hospital Institutional Review Board (IRB) within the timeframes required by hospital policy.

Because buprenorphine has not yet been FDA-approved for treating sickle cell pain crises, and because participants receive a dose determined by the BOIN escalation schedule rather than an individually optimized dose, the study is considered greater than minimal risk. The study team considers inadequate pain relief, rather than a specific drug side effect, to be the most significant risk associated with participation; this risk is addressed by continuing demand-only PCA access throughout the study period.

Data Management and Confidentiality

Study data are stored in a password-protected file and a secure REDCap database, accessible only to the study team, aside from access required for FDA inspection or as needed to publish de-identified results. Each participant is assigned a coded study ID; a master list linking IDs to identities is kept separately, accessible only to the Sponsor-Investigator. No participant-identifying information is included in analyses, publications, or presentations, and REDCap is configured so that survey responses cannot be linked back to the individual who submitted them.

Statistical and Enrollment Considerations

This is a dose-finding pilot study and is not statistically powered to formally test a hypothesis of treatment efficacy. The study plans for approximately 4 dose cohorts of 5 participants each, with the highest tolerated dose expanded to 10 participants, for an anticipated total of approximately 25 enrolled participants. Because not every approached patient will present with a qualifying pain crisis during the enrollment window, up to 50 participants may be consented. Approximately 120 patients ages 12-22 with SCD were seen in the sickle cell clinic and presented to the Emergency Department at the study site in the two years before the study was designed, suggesting the site should be able to consent roughly 40% of eligible patients. The study has received FDA Investigational New Drug (IND) clearance and will start enrollment once final Institutional Review Board (IRB) approval is given. The anticipated enrollment period is approximately 5 years from the date of first participant enrollment, with a primary study completion date expected within approximately 5 years and 30 days, to allow the final participant's 30-day follow-up to be completed. Descriptive statistics will characterize enrollment, safety outcomes, and stability of CO2/vital sign measurements; the frequency of each adverse event or side effect will be reported by dose level; and the dose-response relationship for opioid sparing will be explored through visual inspection of individual trends and area-under-the-curve analysis within each dose cohort.

Inclusion criteria

• SCD diagnosis (confirmed by Hemoglobin electrophoresis prior to consent)
• 12-22 years of age who present for acute sickle cell pain crisis
• Weight > 50kg
• Negative pregnancy test during index admission for patients of childbearing potential

Exclusion criteria

• Patient refusal to participate
• Hypersensitivity (e.g. anaphylaxis) to buprenorphine
• Lack of informed consent or assent
• < 12 years of age
• Weight < 50kg
• Significant respiratory depression
• Presence of gastrointestinal obstruction, including paralytic ileus
• History of seizures
• Presence of shock physiology
• Severe hepatic impairment (Child-Pugh score of C or worse)
• Concurrent benzodiazepine or sedative hypnotics unless use is chronic (patients on a benzodiazepine or sedative-hypnotic for ≥30 days prior to admission may be enrolled with enhanced monitoring; newly initiated agents during the admission are exclusionary)
• Concurrent strong CYP3A4 inhibitors/inducers
• Current Monoamine Oxidase Inhibitor (MAOI) use or use within 14 days
• Active breastfeeding