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.

 致编辑：

镰状细胞病（SCD）是最常见的临床相关遗传性血液疾病，导致器官功能障碍、急性和慢性疼痛以及早期死亡。 ^{1, 2}急性疼痛发作（也称为镰状细胞危象）在 SCD 中很常见，据报道超过 50% 的成年人有慢性疼痛。 SCD 的大部分急性护理是由急性疼痛发作 (APE) 引起的，这通常会导致入院，增加其他并发症的风险，包括急性胸部综合征、静脉血栓形成和感染。

尽管目前的指南规定对 APE 使用侵袭性静脉阿片类药物， ^{3 但}它们也强调了避免慢性阿片类药物治疗 (COT) 的重要性。 COT 的潜在副作用包括阿片类药物引起的痛觉过敏 (OIH)、情绪紊乱和便秘。尽管有这一建议，但尽管结果不令人满意，包括频繁去急诊科 (ED) 表明疗效低于标准，但仍会开出 COT。

丁丙诺啡或丁丙诺啡/纳洛酮已成为完全激动剂阿片类药物的潜在替代品，用于治疗 SCD 的慢性疼痛。丁丙诺啡是一种非选择性混合激动剂-拮抗剂阿片受体调节剂（部分 mu 阿片受体激动剂，具有针对 kappa 和 delta 阿片受体的拮抗剂活性），经 FDA 批准用于治疗疼痛。混合激动剂-拮抗剂作用可缓解疼痛，同时限制用药过量的风险，并可能避免其他副作用。 David M 等人在约翰霍普金斯大学发表的结果⁴表明，在一项正式研究中，丁丙诺啡可有效用于 SCD 患者，该研究采用门诊丁丙诺啡诱导结合强化 SCD 跨学科管理（临床试验 NCT03492099）。他们的协议在此被命名为“大卫-卡罗尔协议”，需要在其他 SCD 中心进行探索。

这是一份关于我们成人综合 SCD 中心针对 SCD 和慢性疼痛患者的“大卫-卡罗尔方案”在现实世界中的适应情况的回顾性报告。该报告详细介绍了从 COT 过渡到丁丙诺啡的患者，并包括现实世界实施的成功和失败。我们还为接受变革性护理治疗（同种异体干细胞移植或基因治疗）并转向丁丙诺啡的患者亚群提供了有希望的结果。

这是 IRB 批准的回顾性图表审查，旨在评估 SCD 中“大卫-卡罗尔协议”的实际实施情况。人口统计数据包括 SCD 表型、SCD 治疗方案、伴随药物、处方药监测计划数据和医疗保健利用数据。所有受试者均已确诊患有 SCD，于 2020 年 9 月至 2022 年 8 月在 SCD 中心就诊，并从 COT 过渡到丁丙诺啡/纳洛酮或丁丙诺啡以治疗慢性难治性疼痛。

尽管采用了最佳的 SCD 管理（慢性红细胞输血疗法 (CRCT)、羟基脲和/或克赞利珠单抗）和不断增加的 COT 剂量，但大多数被确定过渡到丁丙诺啡的患者仍反复进行急性护理就诊。一小部分患者接受了变革性治疗，但仍然经历移植后疼痛。所有患者均被要求在开始使用丁丙诺啡前至少 12 小时停用所有完全激动剂阿片类药物。

由于这是 David-Carroll 协议的现实世界实施，因此该协议针对该患者群体进行了调整。因此，大多数患者在门诊时开始使用丁丙诺啡并进行密切随访，但两名患者在因 APE 住院期间使用微剂量方法开始使用丁丙诺啡。另外两名患者由于交通问题开始在家接受治疗。最后，五名参与者在变革性疗法后开始使用丁丙诺啡-纳洛酮。所有患者随访均包括前 8 周每周一次的随访，结合面对面和远程医疗就诊的方式进行。所有患者均使用临床阿片戒断量表（COWS）进行监测，并评估疼痛、恶心、瘙痒、嗜睡或其他问题。

丁丙诺啡的平均起始剂量为 10.15 毫克/天 (SD = 5.03)。最初建议舌下含服给药，从 4 mg/1 mg BID 到 TID，并根据参与者对治疗的反应（包括疼痛等级和戒断症状）调整剂量。每周给患者开处方，以便有效地调整剂量并在需要时进行更改。

最初 8 周后，大多数患者的预约改为每 2 周一次，然后每 4 周一次。每个患者的个性化护理计划都记录在电子病历中，详细说明了管理变化以及未来 APE 的相关治疗建议。对于使用丁丙诺啡的患者，其急性疼痛管理包括静脉注射/肌肉注射丁丙诺啡、静脉注射对乙酰氨基酚或酮咯酸（如果适用）、补水以及在需要时（即如果疼痛缓解不足）选择改用全激动剂阿片类药物治疗。患者被告知这些变化，并可以通知 UAB 卫生系统之外的提供者。

医疗保健利用率是通过图表审查获得的，并比较了诱导前 6 个月与诱导后 6 个月的情况。当患者被视为 UAB 医疗保健系统的一部分或按照报告（如果在 UAB 以外的机构就诊）时收集数据。如果在急诊就诊、输液/日间医院就诊或住院期间接受了疼痛管理，则包括急性就诊。非急性就诊包括常规 SCD 提供者就诊，包括前 8 周丁丙诺啡随访所需的就诊，以及初级保健或心理学家预约或接受输血或克利珠单抗的就诊。在与 SCD 药剂师合作开始使用丁丙诺啡之前，使用处方药监测计划 (PDMP) 计算口服吗啡当量 (OME)。总剂量根据 30 天期间开出的药丸数量计算并取平均值。因此，患者可能在不同的日子服用了不同的剂量。

使用 COWS 对患者进行临床随访，以监测戒断情况，COWS 是诱导访视的一部分。在诱导期间每小时和随访期间每周使用 0-10 等级对疼痛评分进行跟踪。然而，这些分数没有被包括在内，因为它们没有出于研究目的而标准化。

纳入 32 名患者，其中超过 50% 为女性。所有人员均被确定为非裔美国人或黑人，其中大多数 (81%) 患有 HbSS。入职时的平均年龄为 29.8 岁 (SD = 5.8)。所有患者均接受 SCD 治疗（50% 服用羟基脲 ± crizanlizumab，28% 接受 CRCT）。

医疗保健治疗和利用变化的结果不包括接受变革性治疗的患者 ( n = 5)、在诱导期后 6 个月之前停用丁丙诺啡的患者 ( n = 4) 以及具有镰状细胞特征的个体 ( n = 1)。如表 1 所示，其余 22 名患者诱导前 6 个月与诱导后 6 个月的比较显示，在转用丁丙诺啡之前，平均每日阿片类药物剂量为 118.08 OME (SD = 80.5)。开始使用丁丙诺啡后和诱导后 6 个月，平均剂量为 13.41 毫克/天 (SD = 6.83)。

急诊科平均使用频率（急诊室和输液就诊）从统计上显着减少，从 10.2 次就诊（诱导前）减少到 4.4 次就诊（诱导后）（ p < .001），表 1。住院率从 1.8 减少诱导前的访问次数增加到诱导后的 0.3 次访问次数 ( p = .002)。同时，患者的平均非急性随访次数从 4.9 次增加到 8.5 次 ( p < .001)，这可能是由于该方案中丁丙诺啡监测需要每周进行一次随访。

32 人中有 5 人（16%）接受过干细胞移植或基因治疗。 3 名患者在开始使用丁丙诺啡/纳洛酮前超过 12 个月接受了单倍体移植，但所有患者均持续疼痛，并仍处于 COT 状态并持续进行急性护理就诊。这些患者很容易过渡到丁丙诺啡，疼痛显着改善，截至本报告没有进一步的急性护理就诊。两名患者接受了基因治疗。尽管生物反应令人印象深刻，但一名患者持续频繁出现急性疼痛，在开始服用丁丙诺啡/赛博松后疼痛减轻。该子样本中的最后一名患者在植入（基因治疗）后立即转为丁丙诺啡/赛博松，并且表现良好。此后又有两名患者接受了这种治疗。

四名患者选择停止丁丙诺啡治疗，其中一名患有 HbSC 疾病且长期患有慢性疼痛，但她选择恢复之前的治疗（美沙酮）。两名患者有副作用（疲劳/恶心），一名患者有交通问题。

这是一项回顾性研究，详细介绍了丁丙诺啡大卫-卡罗尔方案在 SCD 和慢性疼痛患者中的实际实施情况。与之前的研究类似， ⁴我们的结果证明了丁丙诺啡对 SCD 患者的安全性和耐受性，并且患者报告的疼痛和急性护理利用率显着改善。重要的是，这里使用的丁丙诺啡剂量明显处于阿片类药物依赖者所需的剂量范围内（平均 16 毫克/天），高于疼痛患者的典型剂量。 ⁵该方案还适用于接受过变革性疗法并取得类似令人印象深刻结果的人。在所有病例中，COWS 都很轻微，不需要治疗。值得注意的是，所有患者均继续接受 SCD 修饰治疗。此外，这些患者都被邀请去看嵌入的心理学家，并接受共病情绪障碍的评估/和/或接受治疗。

这些结果提出了其他几个重要观点。 1. 可能需要适应当地环境才能在其他 SCD 中心广泛实施该协议。 2. 医疗服务提供者必须意识到患有 SCD 的患者可能因长期接受全激动剂阿片类药物治疗而发生严重的 OIH。该队列中受影响的个体无法将 OIH 与“正常”SCD 疼痛区分开来，尽管他们之前有过信念。只有当他们服用丁丙诺啡稳定后，他们才能意识到这种区别是如何因他们的痛觉过敏程度而变得模糊的。这一发现需要在未来的研究中通过正式的疼痛实验室测试进行前瞻性评估。此外，在开始使用丁丙诺啡之前，没有捕获有关睡眠的数据；然而，许多患者指出，接受这种治疗后，他们的入睡和保持睡眠的能力得到了显着改善，这凸显了 COT 可能导致的睡眠中断，这也需要在未来的前瞻性研究中进行验证。 3. 鉴于与 SCD 相关的耻辱，SCD 专家对是否给患有阿片类药物使用障碍的个人贴上标签犹豫不决（一些保险机构要求这样做才能获得药物）。 ⁶因此，患者开始害怕丁丙诺啡，因为他们可能像过去一样被贴上“瘾君子”的标签。 ⁷这种担忧在该队列中也很普遍，需要在治疗开始时进行公开讨论。

本报告详细介绍了大卫-卡罗尔方案在 SCD 患者中实际使用丁丙诺啡的情况。我们的 SCD 中心安全有效地使用丁丙诺啡与之前的其他报告一致。此外，这是大卫-卡罗尔方案在现实世界中实施的回顾性报告，不是前瞻性或随机研究，因此我们在本报告中描述的措施中存在与缺失数据和数据分析相关的局限性。尽管如此，这些发现强调了未来进行更大规模的实施研究的重要性，以确定哪些人最有可能成功接受这种治疗，以及中心如何在当地调整该方案。