Can you provide any evidence for the use of buprenorphine in patients with sickle cell disease? Particularly data for patients in acute pain crisis?

Comment by InpharmD Researcher

While limited to retrospective analyses and case reports, emerging evidence documents the use of buprenorphine in patients with sickle cell disease (SCD), particularly in managing SCD-related chronic pain. Available evidence suggests transitioning patients from as-needed or frequent intravenous (IV) opioids to buprenorphine, with or without naloxone, reduces both acute care utilization and daily opioid use while improving overall clinical outcomes.

Background

A 2020 guideline for acute and chronic pain management in patients with sickle cell disease (SCD) by the American Society of Hematology (ASH) suggests tailored opioid therapy, when indicated, for adults and children with SCD in the acute care setting (adults: conditional recommendation, moderate certainty; children: conditional recommendation, low certainty). The ASH also suggests a short course (5 to 7 days) of nonsteroidal anti-inflammatory drugs (NSAIDs) in addition to opioids for acute pain (conditional recommendation, low certainty), and regional anesthesia for localized pain (conditional recommendation, low certainty). For acute pain related to SCD in hospitalized adult and pediatric patients, adjunctive subanesthetic ketamine infusion is suggested with refractory pain or after opioid monotherapy is deemed ineffective (conditional recommendation, low certainty). However, due to an absence of data, ASH guidelines were unable to derive recommendations for buprenorphine use for patients with pain associated with SCD. The panel followed with research priorities, which included a need for comparative-effectiveness studies between full agonist opioids and partial agonist opioid therapy, such as buprenorphine. [1]

A 2020 review explored the multifaceted aspects of chronic pain management in patients with SCD, particularly focusing on the challenges of distinguishing pain types and treatment limitations. Chronic pain in SCD often coexists with mental health disorders, including depression and anxiety, further complicating treatment. The inadequacy of chronic opioid therapy (COT) as an optimal treatment strategy for SCD-related chronic pain is noted, due to its association with opioid-induced hyperalgesia, opioid toxicity, and opioid withdrawal symptoms, which are often misdiagnosed as vaso-occlusive crisis (VOC) symptoms, leading to frequent acute care utilization. The review analyzed two real-world case studies where treatment regimens focused on identifying non-SCD-related contributors to pain and addressing opioid dependency issues through the careful use of sublingual buprenorphine/naloxone and optimizing SCD-modifying therapies, such as hydroxyurea or L-glutamine. In one case where a 25-year-old African American woman with SCD and diagnosis of physiologic opioid dependence and cyclic opioid withdrawal was transitioned from as-needed oxycodone and frequent intravenous (IV) opioids to sublingual buprenorphine/naloxone, the patient’s acute care use significantly decreased, hydroxyurea adherence improved, Hb F rose from 8% to 42% over 12 months, and no ED visits during this 12-month period. Despite a lack of strong evidence supporting buprenorphine products for chronic pain in SCD, buprenorphine/naloxone may be worth considering for patients with SCD on COT who have a high opioid risk score, are experiencing cyclic opioid withdrawal, or meet criteria for physiologic opioid dependence. [2]

References:

[1] Brandow AM, Carroll CP, Creary S, et al. American Society of Hematology 2020 guidelines for sickle cell disease: management of acute and chronic pain. Blood Adv. 2020;4(12):2656-2701. doi:10.1182/bloodadvances.2020001851
[2] ​​Osunkwo I, O'Connor HF, Saah E. Optimizing the management of chronic pain in sickle cell disease. Hematology Am Soc Hematol Educ Program. 2020;2020(1):562-569. doi:10.1182/hematology.2020000143
Literature Review

A search of the published medical literature revealed 6 studies investigating the researchable question:

Can you provide any evidence for the use of buprenorphine in patients with sickle cell disease? Particularly data for patients in acute pain crisis?

Level of evidence

C - Multiple studies with limitations or conflicting results  Read more→


Please see Tables 1-6 for your response.

 

"Buprenorphine, It Works so Differently": Adults with Sickle Cell Disease Describe Transitioning to Buprenorphine for Treatment of Chronic Pain
Design

Qualitative descriptive study

N= 13
Objective

To explore perspectives on buprenorphine for chronic pain in sickle cell disease (SCD)
Study Groups

All (N= 13)
Inclusion Criteria

Age 18 years or older, diagnosis of SCD, taking buprenorphine now or in the past, English fluency, capacity to consent
Exclusion Criteria

None specified
Methods

Interviews were recorded, transcribed, and analyzed using thematic analysis; participants completed one-on-one audio-recorded telephone interviews.
Duration

Between December 2020 and April 2022
Outcome Measures

Perspectives on buprenorphine, functional and relational changes
Baseline Characteristics  

All (N= 13)

Gender

 9 women, 4 men

Age, years

 26 to 60 

Ethnicity

Black

 

13/13

Full agonist opioid regimens before buprenorphine

 60 to 500 oral morphine milligram equivalents (MME) daily
Taking buprenorphine at the time of interview

11/13

Buprenorphine treatment duration, months

 33 ± 18 (range 7 to 78)
Results Major Themes

All (N= 13)
Readiness for change Participants described dissatisfaction with full agonist opioids
Navigating uncertainty with autonomy Participants navigated ambivalence, fear, and hope when deciding to try buprenorphine
Relationship changes Participants described transformed relationships to pain medications and SCD care
Unchanged dimensions of life and care Some social experiences and structural barriers persisted after switching to buprenorphine
Approaching patients about buprenorphine Participants thought patients on daily opioids and/or with frequent acute care visits should be offered buprenorphine
Adverse Events

One participant stopped buprenorphine after developing wheezing; another described buprenorphine as ineffective for frequent acute pain crises
Study Author Conclusions

Buprenorphine resulted in functional improvements for most participants, suggesting that chronic, high dose full agonist opioid therapy is a risk factor for poor quality of life for some adults with SCD. However, buprenorphine does not resolve all SCD-related pain challenges, and participants continued to face barriers to optimal pain management.
Critique

The authors claim that this is the first qualitative study of buprenorphine in people with SCD, with detailed thematic analysis and a comprehensive approach to SCD care. Yet, this is a single-center study, with the potential for self-selection bias, conducted during the COVID-19 pandemic, which may have affected recruitment and participants' perception of improvements in functioning; retrospective interviewing may introduce recall bias.

 

References:

Prince E, Loeser P, Early M, Carroll CP, Lanzkron S, Pecker LH. "Buprenorphine, It Works so Differently": Adults with Sickle Cell Disease Describe Transitioning to Buprenorphine for Treatment of Chronic Pain. J Pain. 2024;25(3):632-641. doi:10.1016/j.jpain.2023.09.014

 

Real-world Implementation of the David-Carroll Buprenorphine Protocol for Pain Management in Sickle Cell Disease

Design

Retrospective chart review

N= 32

Objective

To evaluate the real-world implementation of the “David–Carroll Protocol” in sickle cell disease (SCD)

Study Groups

All patients (N= 32)

Inclusion Criteria

Patients with confirmed SCD, transitioned from chronic opioid therapy (COT) to buprenorphine/naloxone or buprenorphine for management of chronic, refractory pain

Exclusion Criteria

Receiving transformative therapy, discontinuation of buprenorphine prior to 6-month post induction period, having sickle cell trait

Methods

 Patient data were compiled via retrospective chart review. The "David-Carroll Protocol" involves outpatient induction of buprenorphine combined with intensive interdisciplinary management.

Duration

Treated from September 2020 to August 2022

Outcome Measures

Efficacy and safety

Baseline Characteristics

  

All patients (N= 32)

 

  

Age, years

 29.8    

Female

>50%     

Hemoglobin SS (HbSS)

 81%    

Results

Endpoint

Pre-induction

Post-induction

Mean difference value; p-Value

Opioid dosage, OME

 118.1 ± 80.5 - -

Buprenorphine dosage, mg/day

 10.15 ± 5.0 13.4 ± 6.8 3.3 mg; 0.002

Acute care

6-month ED visit

6-month infusion visit

6-month acute care visit

6-month hospitalization

 

3.5 ± 5.2

6.7 ± 7.6

10.2 ± 9.4

1.8 ± 2.3

 

1.2 ± 1.9

3.2 ± 4.3

4.4 ± 5.4

0.3 ± 0.7

 

-2.3; 0.027

-3.5; <0.001

-5.9; <0.001

-1.5; 0.002

Non-acute care

6-month routine care follow-up visits

 

4.9 ± 3.3

 

8.5 ± 3.5

 

3.5; <0.001

Data provided for patients continuing buprenorphine for ≥6 months without transformative therapy (n = 22)

Adverse Events

 N/A

Study Author Conclusions

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.

InpharmD Researcher Critique

This study is subject to inherent limitations of a retrospective trial, including small sample sizes and potential missing data. 



References:

Torres C, Galadanci N, Osborn J, Kanter J. Real-world implementation of the David-Carroll buprenorphine protocol for pain management in sickle cell disease. Am J Hematol. 2024;99(9):1834-1836. doi:10.1002/ajh.27407

Converting adults with sickle cell disease from full agonist opioids to buprenorphine: A reliable method with safety and early evidence of reduced acute care utilization
Design

Retrospective study

N= 36 
Objective

To assess the safety and efficacy of converting adults with sickle cell disease (SCD) from full agonist opioids to buprenorphine
Study Groups

Standard outpatient protocol group (n= 30)

Inpatient induction group (n= 6)
Inclusion Criteria

Adults over 18 years with SCD, sufficient medical insurance, frequent acute pain visits despite disease-modifying therapy, inadequate pain control despite chronic opioid therapy (COT), or inability to wean off full agonist opioids without intolerable withdrawal symptoms
Exclusion Criteria

Current illicit drug use (other than cannabinoids), pregnancy, known hypersensitivity to buprenorphine
Methods

Participants underwent opioid dose reduction to ≤90 mg oral morphine equivalents (OME) before induction. For the standard outpatient protocol group, inductions involved holding opioids 12-24 hours prior, assessing withdrawal using the Clinical Opioid Withdrawal Scale (COWS), and administering buprenorphine sublingually until withdrawal symptoms were controlled. The inpatient induction group followed similar principles but was conducted during medical stays.

Sublingual buprenorphine doses were standardized to equivalents of the Subutex® /Suboxone® preparations, assuming 5.7 mg of Zubsolv® was equivalent to 8 mg of Subutex®.
Duration

6 months follow-up
Outcome Measures

Acute care utilization (ED visits, SCIC visits, hospital admissions), pain intensity, withdrawal symptoms (COWS), buprenorphine dose, adverse events, discontinuation rates
Baseline Characteristics   All Inductions (n= 36) Outpatient (n= 30)  
Inpatient (n= 6) p-Value (Out vs. In) 
Age 37.31 (10.31) 36.07 (9.85) 43.5 (11.18) 0.176
Female 66.67% 60.00% 100% 0.155
Sickle cell anemia 80.56% 80.00% 83.33% 1.000
Baseline opioid dose 158.15 (109.89) 143.3 (93.88) 232.38 (159.61) 0.237
Acute visits pre-induction 10.5 (11.35) 11.03 (12.18) 7.83 (5.56) 0.329
Induction opioid dose 79.48 (62.6) 69.27 (49.12) 130.52 (98.39) 0.192
Pain pre-induction 6.94 (1.96) 6.87 (2.11) 7.33 (0.82) 0.370
Pain post-induction 4.39 (2.62) 4.03 (2.54) 6.17 (2.48) 0.096
COWS pre-induction 8.89 (3.86) 9 (3.57) 8.33 (5.47) 0.784
COWS post-induction 3.36 (2.49) 3.17 (2.29) 4.33 (3.39) 0.450
Buprenorphine dose 12.12 (5.41) 11.21 (5.03) 16.67 (5.32) 0.054
Results   All Inductions (n= 36) Outpatient (n= 30)  
Inpatient (n= 6) p-Value (Out vs. In)
Adverse events at 3 days 19.44% 23.33% 0.00% 0.451
Discontinued at 6 months 13.89% 16.67% 0.00% 0.666
Acute visits post-induction 2.89 (3.4) 2.7 (3.59) 3.83 (2.23) 0.334
Adverse Events   Relatedness Response
Recurrent/protracted withdrawal Definitely Dose increased
Insurance barrier to outpatient buprenorphine; worsened pain Definitely Daily dosing in infusion center until insurance managed
Tongue numbness and headache Possibly Discontinued
ED visit for treatment Possibly Patient discontinued
Pneumonia, transaminase elevations, and possible transfusion reaction Unlikely Held, then discontinued
Central retinal artery occlusion Unlikely No change
Neck swelling Unlikely No change
Study Author Conclusions

The buprenorphine induction strategy is safe and well-tolerated in patients with SCD, with minimal withdrawal symptoms and a significant reduction in acute care utilization.
Critique

Despite the author's claim that this is the largest sample size study of SCD patients treated with buprenorphine, it is a retrospective study that lacks a control group, has potential biases in patient selection, and includes differences in induction protocols between outpatient and inpatient settings.

 

References:

David MS, Jones J, Lauriello A, et al. Converting adults with sickle cell disease from full agonist opioids to buprenorphine: A reliable method with safety and early evidence of reduced acute care utilization. Am J Hematol. 2022;97(11):1435-1442. doi:10.1002/ajh.26699

 

Transition from Oxycodone to Buprenorphine/Naloxone in a Hospitalized Patient with Sickle Cell Disease: A Case Report

Design

 Case report

Case presentation

A 22-year-old woman with sickle cell disease (SCD) and chronic pain on oxycodone 160 mg every 6 hours (960 morphine mg equivalents) was admitted to the hospital from jail for a vaso-occlusive episode. Since childhood, she has experienced numerous SCD-related complications (i.e., vaso-occlusive episodes, acute chest syndrome, chronic pain). Opioid treatment started during adolescence, with doses escalating due to ineffectiveness for pain management, causing side effects (i.e., severe constipation and sedation) that impaired her ability to perform enjoyed activities. Attempts to taper opioids led to frequent hospitalizations for vaso-occlusive episodes after interrupted doses, leading to discharges on higher opioid doses. The patient did not readily engage with a multidisciplinary sickle cell disease team and was not receiving evidence-based treatments like hydroxyurea. The patient was incarcerated at age 20, where opioid prescribing was continued by Jail Health clinicians.

During this hospitalization, the patient was managed with intravenous (IV) hydromorphone 4 mg every 6 hours, as needed, in addition to her outpatient dose of oxycodone 160 mg every 6 hours. The patient stated a desire to discontinue opioids due to a lack of efficacy, perceived different treatment due to using high-dose opioids, and family history of substance use disorder. Due to the patient's inquiry in buprenorphine for chronic pain, the inpatient addiction consultation service was counseled on day 2 for a potential microdose buprenorphine transition.

On day 5, while the patient was still experiencing acute on chronic pain, buprenorphine was initiated with a gradual microdose, starting on a 20 mcg/hour patch while full agonist opioids were continued. Over the next 5 days, buprenorphine was slowly increased, and oxycodone was tapered. All dosing adjustments were made with shared decision-making with the clinicans and patient. The maximum Clinical Opioid Withdrawal Scale (COWS) score was 7 on day 10, which occurred after swallowing buprenorphine/naloxone tablets instead of taking them sublingually. The patient remained hospitalized for several days for symptom management and gradually titrated buprenorphine/naloxone to a dose of 40/10 mg per day (in four divided doses). Despite mild to moderate withdrawal symptoms, the patient tolerated the transition well with adjunctive therapy (i.e., loperamide, clonidine, diphenhydramine, acetaminophen, ibuprofen, trazodone) and non-pharmacological techniques (i.e., mind-body relaxation strategies, music, and coloring books). 

On hospital day 16, the patient was discharged back to jail. She was briefly readmitted to the hospital due to acute worsening of pain after a missed dose of buprenorphine in the jail. During subsequent hospitalization, buprenorphine/naloxone was increased to 48/12 mg daily in four divided doses. After close coordination with Jail Health Services to ensure timely dosing, the patient experienced marked improvement in pain levels, reporting 0/10 pain levels at 4 months after starting buprenorphine, as well as improved mood and function.

Study Author Conclusions

 Our case report suggests that microdose transition from chronic, high-dose full agonist opioids to buprenorphine in patients with sickle cell disease, even during a hospitalization for an acute vaso-occlusive episode, may be safe, effective, and feasible. More research is needed to understand the optimal transition strategies and dosing of buprenorphine among people with sickle cell disease.
References:

Leyde S, Suen L, Pratt L, DeFries T. Transition from Oxycodone to Buprenorphine/Naloxone in a Hospitalized Patient with Sickle Cell Disease: A Case Report. J Gen Intern Med. 2022;37(5):1281-1285. doi:10.1007/s11606-021-07295-2

 

Buprenorphine for Chronic Pain in a Pediatric Patient With Sickle-Cell Disease

Design

 Case report

Case presentation

An 11-year-old female patient with a history of sickle cell disease (SCD) and multiple previous hospitalizations for acute pain crisis presented with acute vaso-occlusive crisis (VOC). Symptoms included worsened head, chest and arm pain during her outpatient red cell transfusion. Her home pain medication regimen included methadone 5 mg TID, scheduled hydromorphone 4 mg Q4H, acetaminophen 500 mg TID, nortriptyline 30 mg at bedtime and ibuprofen 300 mg TID, all administered orally. Due to uncontrolled pain with hydroxyurea, L-glutamine, chronic red cell infusions, and methadone, her outpatient providers planned to initiate buprenorphine induction. However, due to her VOC presentation, she was admitted and treated for pain control with intravenous hydration, hydromorphone 2 mg PO Q2H PRN, and IV ketorolac.

Once her pain was better controlled, buprenorphine was administered in the form of buprenorphine/naloxone 2 mg/0.5 mg sublingual (SL) films, cut to facilitate dose titration. Buprenorphine was started at 0.5 mg SL BID (day 0) and titrated slowly over 8 days as the following total daily doses: 1 mg (day 1), 2 mg (day 2), 3 mg (day 3), 4mg (days 4-5), 6 mg (days 13-14), and 8 mg (days 8). Dose titrations continued based on the patient's pain response. Buprenorphine 2 mg SL BID (8 mg daily) was continued while hospitalized. However the patient required hydromorphone PRN and a blood transfusion due to worsening bilateral arm pain, increased fatigue, and a 2 g drop in hemoglobin. Due to concern for acute VOC due to worsening abdominal pain within 48 hours, hydromorphone doses were increased and a ketamine infusion was initiated. During this time buprenorphine was continued.

Once pain was under control, ketamine was discontinued and the patient was discharged on buprenorphine 2mg SL QID with a new home regimen of hydromorphone 3 mg TID with 2 mg Q8H PRN, duloxetine 60 mg daily, acetaminophen 500 mg TID, and ibuprofen 600 mg TID PRN, all administered orally. Hydromorphone PRN was weaned off after discharge and buprenorphine 8 mg was continued, but changed from QID to TID. Following discharge, the patients reported improved functionality and improved pain control, and rate of hospitalization for VOC was reduced from previous 1.57 admissions per month to 0.86 per month. Average daily oral morphine equivalents (OMEs) were reduced from 136 mg to 96 mg, this excluded methadone and buprenorphine. 

Study Author Conclusions

This case describes a successful rotation to buprenorphine using a micro-dosing regimen for a pediatric patient with chronic SCD pain. It highlights the feasibility of this approach for other pediatric patients with chronic pain, especially those with SCD. In this case, buprenorphine proved to be a safe and efficacious alternate to chronic opioid therapy with full agonists for an 11-year-old with chronic SCD pain. The patient in this case demonstrated improved functionality, decreased OMEs, and lower healthcare utilization.
References:

Irwin M, Gunther W, Keefer P, et al. Buprenorphine for Chronic Pain in a Pediatric Patient With Sickle-Cell Disease. J Pain Symptom Manage. 2021;62(5):1086-1091. doi:10.1016/j.jpainsymman.2021.04.007

 

Ambulatory microdose induction of buprenorphine-naloxone in two adolescent patients with sickle cell disease

Design

 Case series 

Case presentations

A 2020 case series details the use of ambulatory microdose induction of buprenorphine-naloxone in two adolescent patients suffering from sickle cell disease (SCD) and persistent pain. Both patients had a history of high opioid use but expressed interest in reducing their dependence on full-agonist opioids. The report outlines the successful implementation of the Bernese method, a microdose protocol that allows buprenorphine-naloxone to be gradually introduced without discontinuing full opioid agonists and, crucially, without triggering opioid withdrawal.

The first patient, a 17-year-old male, transitioned from methadone and oxycodone to buprenorphine-naloxone over an 8-day period, reporting no withdrawal symptoms and improved pain control.

Buprenorphine-naloxone outpatient microdosing protocol - Case 1
Day Buprenorphine-naloxone dose Full agonist opioid daily dose
1-3 0.5 mg-0.125 mg sublingual (SL) daily 12.5 mg methadone; 37.5 mg oxycodone
4 0.5 mg-0.125 mg SL twice daily 12.5 mg methadone; 37.5 mg oxycodone
5 1 mg-0.25 mg SL twice daily 12.5 mg methadone; 37.5 mg oxycodone
6 1 mg-0.25 mg SL three times daily 12.5 mg methadone; 37.5 mg oxycodone
7 2 mg-0.5 mg SL twice daily 12.5 mg methadone; 37.5 mg oxycodone
8 2 mg-0.5 mg SL three times daily 0 mg methadone; 0 mg oxycodone

The second patient, a 19-year-old male, transitioned from oxycodone using a similar protocol and also experienced minimal withdrawal symptoms, successfully reducing his opioid intake while maintaining active pain management with buprenorphine-naloxone for six months post-induction. Regarding adverse events, case 1 reported two migraines during induction, while case 2 had sweats, yawning, chills post-induction. Yet, both patients achieved significant reductions in opioid use, improved pain outcomes, and lower healthcare utilization following the microdose induction protocol. According to the report, the approach was particularly beneficial as it allowed the adolescents to continue their daily activities, such as school and work, without the need for hospitalization or opioid withdrawal.

Buprenorphine-naloxone outpatient microdosing protocol - Case 2
Day Buprenorphine-naloxone dose Full agonist opioid daily dose
1 0.5 mg-0.125 mg SL daily 120 mg oxycodone ER; 60 mg oxycodone
2 0.5 mg-0.125 mg SL twice daily 120 mg oxycodone ER; 60 mg oxycodone
3 1 mg-0.25 mg SL twice daily 120 mg oxycodone ER; 60 mg oxycodone
4 1 mg-0.25 mg SL three times daily 120 mg oxycodone ER; 60 mg oxycodone
5 2 mg-0.5 mg SL twice daily 120 mg oxycodone ER; 60 mg oxycodone
6 2 mg-0.5 mg SL three times daily 120 mg oxycodone ER; 60 mg oxycodone
7 4 mg-1 mg SL three times daily 0 mg oxycodone ER; 0 mg oxycodone

 

Study Author Conclusions

The buprenorphine-naloxone microdose protocol in both cases represents a promising method for transitioning opioid-dependent SCD patients away from full agonist opioids, mitigating the risks of opioid withdrawal and addressing chronic pain in a controlled outpatient setting. Despite the limited sample size, the positive outcomes suggest this method could be a viable option for other SCD patients with similar profiles, though further research is warranted to evaluate its broader applicability.

 

References:

Buchheit BM, Joslin T, Turner HN, Wong TE. Ambulatory microdose induction of buprenorphine-naloxone in two adolescent patients with sickle cell disease. Pediatr Blood Cancer. 2021;68(1):e28766. doi:10.1002/pbc.28766