Real‐world implementation of the David–Carroll buprenorphine protocol for pain management in sickle cell disease
Authors: Calia Torres, Najibah Galadanci, Jeremy Osborn, Julie Kanter
Journal: American Journal of Hematology (2024)

To the Editor: Sickle cell disease (SCD) is the most common clinically relevant inherited blood disorder resulting in organ dysfunction, acute and chronic pain, and early mortality.1, 2 Acute painful episodes (also known as sickle cell crisis) are common in SCD and chronic pain is reported in over 50% of adults. The majority of the acute care in SCD is caused by acute pain episodes (APE) which often result in hospital admission increasing the risk for other complications including acute chest syndrome, venous thrombosis, and infection. Although current guidelines specify the use of aggressive intravenous opioids for the APEs,3 they also highlight the importance avoiding chronic opioid therapy (COT). Potential side effects of COT include opioid-induced hyperalgesia (OIH), mood disruption, and constipation. Despite this recommendation, COT are still prescribed despite unsatisfactory outcomes, including frequent emergency department (ED) visits suggesting sub-par effectiveness. Buprenorphine or buprenorphine/naloxone has emerged as a potential substitute for full agonist opioids for chronic pain in SCD. Buprenorphine is a non-selective mixed agonist–antagonist opioid receptor modulator (partial mu opioid receptor agonism with antagonist activity against the kappa and delta opioid receptors) that is FDA-approved for the treatment of pain. The mixed agonist–antagonist effect provides pain relief while limiting the risk of overdose and potentially avoiding other side effects. Results published by the David M et al at Johns Hopkins4 demonstrated that buprenorphine can be used effectively in people with SCD in a formal study using outpatient induction of buprenorphine combined with intensive SCD interdisciplinary management (clinical trials NCT03492099). Their protocol named here as the "David–Carroll Protocol," needs to be explored in other SCD centers. This is a retrospective report on the real-world adaptation of the "David–Carroll Protocol" for people with SCD and chronic pain at our Adult Comprehensive SCD Center. This report details patients transitioned from COT to buprenorphine and includes both the successes and failures of real-world implementation. We also present promising results for a sub-population of patients who underwent transformative care treatment (allogeneic stem cell transplant or gene therapy) and transitioned to buprenorphine. This is an IRB-approved retrospective chart review performed to evaluate the real-world implementation of the "David–Carroll Protocol" in SCD. Demographic data included SCD phenotype, SCD-treatment regimen, concomitant medications, Prescription Drug Monitoring Program data, and healthcare utilization data. All subjects had confirmed SCD, were seen from September 2020 to August 2022 at the SCD center and were transitioned from COT to buprenorphine/naloxone or buprenorphine for management of chronic, refractory pain. Most of the patients who were identified to transition to buprenorphine had recurrent acute care visits despite optimal SCD management (chronic red cell transfusion therapy (CRCT), hydroxyurea, and/or crizanlizumab) and escalating doses of COT. A small portion of the patients had received transformative therapies but continued to experience post-transplant pain. All patients were asked to stop all full agonist opioids for at least 12 h prior to starting buprenorphine. As this was a real-world implementation of the David–Carroll protocol, the protocol was adapted for this patient population. Thus, most patients started buprenorphine as outpatient with close follow-up, but two patients initiated buprenorphine while hospitalized for APE using a micro-dosing approach. Two other patients initiated treatment at home due to transportation issues. Finally, five participants started buprenorphine-naloxone following transformative therapies. All patient follow-up included weekly visits for the first 8 weeks using a combination of in-person and telehealth visits. All patients were monitored using a clinical opiate withdrawal scale (COWS) and evaluated for pain, nausea, pruritis, drowsiness or other concerns. The average starting dosage of buprenorphine was 10.15 mg/day (SD = 5.03). Dosing was initially proposed to be taken sublingually starting at 4 mg/1 mg BID to TID and the dosage was adjusted based on participants' response to treatment, including pain ratings and withdrawal symptoms. Patients were given weekly prescriptions in order to effectively titrate their dose and make changes if needed. After the first 8 weeks, most patients' appointments moved to every 2 then every 4 weeks. Each patient had their individualized care plan recorded in the electronic medical record detailing the change in management and associated treatment recommendations for a future APE. For patients on buprenorphine, their acute pain management included treatment with intravenous/intramuscular buprenorphine, intravenous acetaminophen or ketorolac (if applicable), hydration and the option to switch to full-agonist opioid treatment if needed (i.e., if pain relief was insufficient). Patients were informed of these changes and could inform providers outside of the UAB health system. Healthcare utilization was obtained from the chart review and compared from 6-months pre-induction to 6-months post induction. Data was collected when patients were seen as part of the UAB healthcare system or as reported (if seen at a facility outside of UAB). An acute visit was included if pain management was received during an ED visit, infusion/day hospital visit or hospitalization. A non-acute visit included routine SCD provider visits, including those required for buprenorphine follow-up for the first 8-weeks, as well as primary care or psychologist appointments or visits to receive transfusions or crizanlizumab. The Prescription Drug Monitoring Program (PDMP) was used to calculate the oral morphine equivalents (OME) prior to starting buprenorphine in collaboration with the SCD pharmacist. The total dose was calculated based on the number of pills prescribed for the 30-day period and averaged. Thus, patients may have taken different dose on different days. Patients were followed clinically to monitor for withdrawal using the COWS that was administered as part of the induction visit. Pain scores were followed using a 0–10 scale both hourly during induction and weekly during follow-up. However, these scores were not included as they were not standardized for research purposes. Thirty-two patients were included of whom >50% of were female. All identified as African American or Black and the majority (81%) had HbSS. The average age at induction was 29.8 years (SD = 5.8). All patients were receiving SCD therapy (50% were taking hydroxyurea ± crizanlizumab and 28% were on CRCT). Results for changes in healthcare treatment and utilization excludes patients that received transformative therapy (n = 5), discontinued buprenorphine prior to the 6-month post induction period (n = 4) and an individual that had sickle cell trait (n = 1). As seen in Table 1, comparison from 6-months pre-induction to 6-months post-induction for the remaining 22 patients revealed that prior to transitioning to buprenorphine, the mean daily opioid dosage was 118.08 OME (SD = 80.5). After starting buprenorphine and at 6-months post induction, the mean dosage was 13.41 mg/day (SD = 6.83). There was a statistically significant reduction in the mean frequency of acute care utilization (ED and infusion visits) from 10.2 visits (pre-induction) to 4.4 visits (post-induction) (p < .001), Table 1. Hospitalizations decreased from 1.8 visits pre-induction to 0.3 visits post-induction (p = .002). Simultaneously, the patients' mean non-acute follow up visits increased from 4.9 visits to 8.5 (p < .001) likely due to the weekly visits required for buprenorphine monitoring in this protocol. Five (16%) of the 32 individuals had received stem cell transplant or gene therapy. Three patients had undergone haplo-identical transplant >12 months prior to starting buprenorphine/naloxone but all continued pain and remained on COT with ongoing acute care visits. These patients transitioned easily to buprenorphine with significant improvement in pain and no further acute care visits as of this report. Two patients had received gene therapy. Despite an impressive biologic response, one patient had ongoing frequent acute pain which abated upon starting buprenorphine/suboxone. The final patient in this sub-sample, transitioned to buprenorphine/suboxone immediately after engraftment (gene therapy) and did well. Two more patients have since been managed this way. Four patients opted to discontinue buprenorphine treatment including one with HbSC disease and a long history of chronic pain who opted to resume her prior therapy (methadone). Two patients had difficulty with side effects (fatigue/nausea) and one had transportation issues. This is a retrospective study detailing the real-world implementation of the David–Carroll protocol for buprenorphine for people with SCD and chronic pain. Similar to the previous study,4 our results demonstrate the safety and tolerability of buprenorphine in people with SCD with a significant improvement in patient-reported pain and acute care utilization. Importantly, the dose of buprenorphine used here is notably in the range of that required for people with opioid dependence (average of 16 mg/day) which is higher than the typical dose for people with pain.5 The protocol was also adapted for people who had received transformative therapies with similarly impressive results. In all cases, COWS were minimal and did not require treatment. It is important to note that all patients continued to receive SCD-modifying therapy. In addition, these patients were all invited to see the embedded psychologist and were evaluated for/and/or received treatment for co-morbid mood disorder. These results raise several other important points. 1. Adaptation to local environments may be needed to widely implement this protocol in other SCD centers. 2. Providers must be aware of the potential for severe OIH in people with SCD-likely due to long-term exposure to full agonist opioid therapy. Affected individuals in this cohort were unable to differentiate OIH from their "normal" SCD pain despite their prior convictions. Only after they were stable on buprenorphine, could they recognize how this distinction had become blurred by their degree of hyperalgesia. This finding will need to be assessed prospectively in a future study with formal pain-laboratory testing. In addition, data were not captured regarding sleep prior to the initiation of buprenorphine; however many patients noted significant improvements in their ability to fall and stay asleep once on this regimen highlighting the sleep disruption that can be caused by COT which will also require validation in a future prospective study. 3. There is a hesitancy among SCD specialists to label individuals with opioid use disorder given the stigma associated with SCD (this was required by some insurance agencies to obtain the medication).6 Thus, patients became fearful of buprenorphine because they could be labeled as "addicts" as in the past.7 This concern was also prevalent in this cohort and required open discussion at the time of treatment initiation. This report details the adaptation of the David–Carroll Protocol for the real-world use of buprenorphine in people with SCD. The safe and effective use of buprenorphine at our SCD center is consistent with other previous reports. Further, this is a retrospective report of the real-world implementation of David–Carroll protocol and was not a prospective or randomized study, thus we had limitations associated with missing data and data analyses for the measures described in this report. Nevertheless, these findings highlight the importance of a future, larger implementation study to identify which individuals are most likely to be successful with this treatment and how centers can locally adapt this protocol. The authors declare no potential conflict of interest that relates to the research described in this paper. Patient consent was not required as part of the IRB-approved protocol for retrospective chart review. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions. Data S1. Supporting Information. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.