Abstract
Background:
The use of morphine in managing vaso-occlusive crisis (VOC) in patients with sickle cell disease (SCD) can result in significant side effects. Nalbuphine, a mixed agonist–antagonist opioid, may offer an alternative with fewer complications.
Objective:
To compare the efficacy and safety of nalbuphine and morphine in pain management among adult SCD patients presenting with VOC.
Methods:
This retrospective study included adult patients with SCD treated at King Fahad Hospital, Hofuf, Saudi Arabia, between 2019 and 2023. Patients were classified into two groups (receiving morphine and nalbuphine). Pain levels were assessed using the Visual Analog Scale (VAS) at baseline, 1-h, 6-h, and 24-h post-administration. Additional outcomes included the need for rescue medication and discharge rates from the emergency department.
Results:
A total of 234 patients were included (morphine: 120; nalbuphine: 114). The mean age of the cohort was 30.5 ± 8.7 years, and 63.8% were female. Baseline laboratory data indicated mean hemoglobin of 8.5 g/dL and elevated lactate dehydrogenase (576.9 U/L). At 6 h, 10% and 20% of patients on morphine and nalbuphine, respectively, reported no pain (P = 0.013). At 24 h, 30% and 40% of patients on nalbuphine and 15% and 25% on morphine experienced no pain and mild pain, respectively (P = 0.00002). Nalbuphine patients required less rescue medication (41% vs. 59%, P = 0.009) and had higher discharge rates from the emergency department (70% vs. 46%, P = 0.0003). No significant difference was found in the incidence of acute chest syndrome or ICU admissions between the two groups.
Conclusion:
Nalbuphine can be a potential alternative for vaso-occlusive crisis pain management in sickle cell disease patients, as it demonstrated superior efficacy compared with morphine, especially at later time points, with reduced need for rescue medication and earlier discharge.
Keywords: Morphine, nalbuphine, opioid therapy, pain management, sickle cell disease, vaso-occlusive crisis
INTRODUCTION
Sickle cell disease (SCD) includes inherited conditions such as sickle cell anemia, hemoglobin SC (HbSC), and HbSβ-thalassemia, caused by mutations in the hemoglobin subunit β (HBB) gene. Hemoglobin (Hb) is a protein in red blood cells that carries oxygen. The adult form, HbA, consists of two α-globin and two β-globin subunits. A single nucleotide change in HBB produces the sickle Hb (HbS) allele, leading to polymerization under low oxygen, causing red blood cells to sickle and trigger vaso-occlusive episodes. Individuals with one HbS mutation have sickle cell trait, while those with two have SCD.[1]
Between 2000 and 2021, the incidence of SCD in individual countries was stable, yet, worldwide, population growth, primarily in the Caribbean and sub-Saharan Africa, resulted in an increase in the number of children with SCD by 13.7%, reaching 515,000. In addition, the global number of people living with SCD rose by 41.4%, reaching 7.7 million in 2021.[2] In Saudi Arabia, SCD affects 0.26% of the population, with 4.2% carrying the sickle cell trait. The Eastern Province has the highest prevalence, with 1.2% affected and about 17% carrying the trait.[3]
SCD signs typically appear in early childhood, with varying symptom severity. Common initial symptoms include dactylitis, pallor, jaundice, and fatigue due to anemia. SCD is marked by recurrent crises—vaso-occlusive, aplastic, splenic sequestration, and hemolytic—resulting in severe pain, ischemia, and potential organ damage. Acute chest syndrome, characterized by chest pain, fever, and respiratory symptoms, is a major cause of mortality. Complications include a heightened risk of severe bacterial infections, stroke, gallstones, avascular necrosis, priapism, chronic pain, pulmonary hypertension, cardiomyopathy, and chronic kidney failure.[4]
Management of SCD aims at symptom relief, complication prevention, and enhancing quality of life. Initial treatment includes hydration, analgesia, and oxygen for acute pain and hypoxia. Therapeutic options such as hydroxyurea and blood transfusions can improve quality of life, reduce complications, and extend survival. Stem cell transplantation is the only curative option, limited by donor availability.[5] Treatment of vaso-occlusive crisis (VOC) in SCD often uses opioids such as morphine and nalbuphine. Morphine is potent but has adverse effects such as addiction, respiratory depression, constipation, and increased risk of acute chest syndrome (ACS).[6,7] It may also worsen endothelial activation, leading to organ dysfunction.[8] Nalbuphine, a mixed agonist–antagonist opioid, has fewer complications with similar efficacy.[6] However, research comparing their efficacy and safety in VOC management is limited.
This study aims to address this gap by analyzing the efficacy and safety of morphine versus nalbuphine in managing pain crises in patients with SCD. By focusing on comparative outcomes and associated complications, this study seeks to guide clinical decision making and improve patient care in SCD management.
METHODS
Study design, setting, and participants
This retrospective cohort study included adult patients (aged ≥18 years) diagnosed with SCD who were treated at King Fahad Hospital, Hofuf, Saudi Arabia, between January 2019 and December 2023. The study was conducted after receiving ethical approval from the Research Ethics Committee of King Faisal University.
Patients were included if they were admitted for VOC, treated with either morphine or nalbuphine for pain management, received the same dosage and route of administration for morphine or nalbuphine, and had complete medical records available for review. Patients with incomplete medical records, who received both morphine and nalbuphine concurrently during the study period, and with contraindications to either morphine or nalbuphine were excluded.
The administration of morphine and nalbuphine followed predefined hospital protocol, ensuring consistency in dosages and routes of administration. According to this protocol, intravenous administration consisted of either morphine at a dose of 0.1 mg/kg or nalbuphine at a dose of 10–20 mg per 70 kg, with or without non-opioid analgesics. Rescue medication was restricted to half the initial dose and could be repeated up to two times, as needed. Pain assessments, including the Visual Analog Scale (VAS), were routinely documented at predefined time points—baseline, 1-h, and 6-h post-administration in the Emergency Department (ED), and at 24-h post-administration for admitted patients—as part of standard clinical care. Pain intensity was categorized based on the VAS as follows: no pain (0), mild pain (1–3), moderate pain (4–6), and severe pain (7–10). This categorical classification was chosen to align with clinical decision making in pain management, as opioid administration and escalation strategies are typically guided by qualitative pain assessments rather than precise numerical values.
Data collection
Data were extracted from the electronic medical records using a standardized data collection form. For patients with multiple ED visits during the study period, only the first eligible visit was included in the analysis to prevent data duplication and reduce confounding. The following data were collected for each patient:
Demographic: Age, gender, body mass index (BMI), and level of education.
Clinical: Type of SCD, frequency of VOCs, comorbidities, history of stroke, cholecystectomy, splenectomy, previous blood transfusions, use of hydroxyurea, previous ICU admissions, and history of acute chest syndrome.
Pain management: Type of analgesic (morphine or nalbuphine), dosage, duration of treatment, route of administration. Patients were allocated to either the morphine or nalbuphine group based on clinical judgment, considering prior opioid use, response to morphine or nalbuphine, adverse effects, contraindications, and patient preference. Patients who had previously experienced inadequate pain relief or significant side effects with morphine were more likely to receive nalbuphine based on physician recommendation or personal preference. Similarly, those with prior ineffective response or intolerance to nalbuphine were allocated to the morphine group. Treatment decisions were documented in medical records and reviewed to minimize selection bias.
Laboratory: White blood cell count, hemoglobin level, platelet count, mean corpuscular volume (MCV), HbS percentage, lactate dehydrogenase (LDH) levels, blood urea nitrogen (BUN), creatinine levels, total and direct bilirubin levels, aspartate transaminase (AST), and alanine transaminase (ALT) levels.
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Primary outcomes: Efficacy of pain management, assessed by:
Mean pain scores measured by VAS at baseline, 1-h, 6-h post-administration in all patients, and 24-h post-administration for admitted patients
Requirement for rescue medication, as requested by the patient
Discharge status from the emergency room
Secondary outcomes: Safety profiles, including incidence of acute chest syndrome and ICU admissions
We used double data extraction and random audits to ensure accurate information. If there was a conflict, a third data collector would decide whether to include or exclude the patient selected and would correct any incorrect information due to inaccurate collection by the previous data collector.
Statistical analysis
Descriptive statistics were used to summarize demographic and clinical characteristics. Continuous variables were expressed as means ± standard deviations (SD), and categorical variables as frequencies and percentages. The efficacy of morphine versus nalbuphine was compared using repeated measures analysis of variance (ANOVA) for VAS scores, a repeated measures one-way ANOVA was employed to compare the evolution of pain scores across different time points within and between treatment groups. This approach allowed for assessing both intra- and inter-group variations in analgesic efficacy. Safety outcomes were compared using Chi-square tests for categorical variables. A P value of <0.05 was considered statistically significant. All analyses were performed using SPSS version 25.0.
RESULTS
Demographic and clinical characteristics of patients
A total of 834 patients with SCD were treated at King Fahad Hospital during the study period, of which 234 were included after applying the inclusion and exclusion criteria [Figure 1]. As shown in Table 1, most patients were females (63.8%), with a mean age of 30.5 (±8.7) years. In terms of education level, 37.6% had secondary education, with 4.8% having a Master’s degree. Clinically, almost all patients had previous blood transfusions (93.3%), while cholecystectomy and splenectomy were done in 20% and 8.6%, respectively. About one-fourth (23.8%) used hydroxyurea, while about three-fourths (76.7%) had a previous ICU admission. Additionally, 38.0% of patients had a history of acute chest syndrome. Within clinical setting, morphine and nalbuphine were administered to 51.4% and 48.6% of patients, respectively. The study also highlights the recurrent nature of VOC, with patients experiencing an average of 3.2 hospitalizations and 7.3 emergency room visits per year.
Figure 1.
Patient inclusion and categorization flowchart
Table 1.
Characteristics of the patients (n=234)
| Variable | Value, n (%) |
|---|---|
| Gender | |
| Female | 149 (63.8) |
| Male | 85 (36.2) |
| Age (years) | 30.5±8.7 |
| Level of education | |
| Illiterate | 10 (4.3) |
| Primary | 24 (10) |
| Intermediate | 50 (21.4) |
| Secondary | 88 (37.6) |
| Graduation | 51 (21.9) |
| Master | 11 (4.8) |
| History of stroke | |
| Yes | 4 (1.4) |
| No | 230 (98.6) |
| Cholecystectomy | |
| Yes | 47 (20) |
| No | 187 (80) |
| Splenectomy | |
| Yes | 20 (8.6) |
| No | 214 (91.4) |
| Previous blood transfusions | |
| Yes | 218 (93.3) |
| No | 16 (6.7) |
| Hydroxyurea | |
| Yes | 56 (23.8) |
| No | 178 (76.2) |
| Previous ICU admission | |
| Yes | 179 (76.7) |
| No | 55 (23.3) |
| Previous acute chest syndrome | |
| Yes | 89 (38) |
| No | 145 (62) |
| Frequency of hospitalization per year | 3.2 |
| Frequency of emergency visit per year | 7.3 |
ICU – Intensive care unit
Baseline laboratory data for sickle cell disease patients
The multisystemic disease nature of SCD is demonstrated through the baseline laboratory profile of the patients [Table 2]. Blood cell count demonstrates a trend toward leukocytosis (white blood cells: 10.6 × 109/L ± 3.16), indicative of chronic inflammation. Hemoglobin levels (8.5 ± 1.1 g/dL) suggest hemolytic anemia, a hallmark of SCD due to its impact on red blood cell (RBC) fragility and lifespan. Platelet count (355.2 × 109/L ± 86.3) point toward thrombocytosis, possibly a compensatory response to ongoing hemolysis and inflammation. The MCV of 90.53 (±4.4) fL was within or slightly above the normal range, suggesting the presence of macrocytosis or normocytosis with increased reticulocyte count (immature RBCs), as the body attempts to compensate for anemia through erythropoiesis.
Table 2.
Baseline laboratory data for sickle cell disease patients
| Variable | Mean±SD |
|---|---|
| Leukocyte count (×109/L) | 10.6±3.2 |
| Hemoglobin level (g/dL) | 8.5±1.1 |
| Platelet count (×109/L) | 355.2±86.3 |
| MCV (fL) | 90.5±4.4 |
| HbS (%) | 79.4±10.6 |
| LDH (U/L) | 576.9±183.8 |
| BUN (mmol/L) | 5.0±1.6 |
| Creatinine (μmol/L) | 79.9±19.4 |
| Total bilirubin (μmol/L) | 27.3±9.3 |
| Direct bilirubin (μmol/L) | 10.1±3.9 |
| AST (IU/L) | 43.2±18.9 |
| ALT (IU/L) | 36.6±16.5 |
AST – Aspartate transaminase; ALT – Alanine transaminase; BUN – Blood urea nitrogen; MCV – Mean corpuscular volume; HbS – Sickle hemoglobin; LDH – Lactate dehydrogenase, SD – Standard deviation
HbS percentage (79.4% ±10.6%) underscores the genetic underpinning of SCD, with elevated levels of sickle hemoglobin (HbS) leading to erythrocyte sickling. Elevated LDH levels (577 ± 183.8 U/L) reflect high rates of intravascular hemolysis, a characteristic feature of SCD. Kidney function appears mostly normal with BUN levels averaging 5.0 (±1.6) mmol/L and creatinine at 79.9 (±19.4) μmol/L. Bilirubin levels highlight hyperbilirubinemia, a consequence of increased RBC breakdown (total bilirubin: 27.3 ± 9.3 μmol/L; direct bilirubin: 10.11 μmol/L ± 3.86). Liver enzymes (AST: 43.2 ± 18.9 IU/L; ALT: 36.6 ± 16.6 IU/L) may be elevated, indicating potential hepatocellular injury, which can be associated with SCD complications.
Result of primary outcome efficacy
Initially, both groups reported mostly moderate pain [Table 3] [Figure 2]. At 1 h, nalbuphine showed a trend toward more patients reporting “no pain,” but this difference was not significant (P = 0.054). By 6 h and 24 h, the nalbuphine group had significantly more patients reporting “no pain” compared with morphine (P = 0.013 and 0.00002, respectively) [Table 3]. Morphine patients required rescue medication more frequently (P = 0.009) [Table 3] [Figure 3], and the nalbuphine group had significantly higher discharge rates (P = 0.0003).
Table 3.
Comparison of morphine and nalbuphine efficacy in pain management and outcome metrics
| Time point | Morphine (n=120) (%) | Nalbuphine (n=114) (%) | P |
|---|---|---|---|
| Baseline | |||
| No pain | 1 | 1 | 0.713 |
| Mild pain | 1 | 1 | |
| Moderate pain | 89 | 84 | |
| Severe pain | 9 | 14 | |
| 1 h | |||
| No pain | 5 | 10 | 0.054 |
| Mild pain | 10 | 20 | |
| Moderate pain | 70 | 60 | |
| Severe pain | 15 | 10 | |
| 6 h | |||
| No pain | 10 | 20 | 0.013 |
| Mild pain | 20 | 30 | |
| Moderate pain | 60 | 40 | |
| Severe pain | 10 | 10 | |
| 24 h* | |||
| No pain | 15 | 30 | 0.00002 |
| Mild pain | 25 | 40 | |
| Moderate pain | 50 | 20 | |
| Severe pain | 10 | 10 | |
| Outcome metrics | |||
| Requested rescue medication | 59 | 41 | 0.009 |
| Discharged from ER** | 46 | 70 | 0.0003 |
*Admitted group; **After 6 h observation. ER – Emergency room
Figure 2.
Comparison of morphine and nalbuphine efficacy in pain management
Figure 3.
Comparison of morphine and nalbuphine efficacy in requested rescue drugs and discharge from emergency department. ER – Emergency room
Pain management
At baseline, there was no significant difference in pain levels between the two groups (P = 0.713), with both groups having similar distributions: 1% (no pain), 1% (mild pain), 89% (moderate pain), and 9% (severe pain) for morphine; and 1% (no pain), 1% (mild pain), 84% (moderate pain), and 14% (severe pain) for nalbuphine.
At 1-h post-administration, nalbuphine showed a trend toward better pain relief, with 10% of patients reporting no pain and 20% reporting mild pain, compared to 5% and 10%, respectively, in the morphine group. Although this difference was not statistically significant (P = 0.054), it indicated a potential advantage of nalbuphine.
The efficacy of nalbuphine became significant at 6 h (P = 0.013), with 20% and 30% of patients reporting no or mild pain, in contrast to 10% and 20% in the morphine group, respectively. By 24 hours, the difference was highly significant (P = 0.00002), with 30% and 40% of patients on nalbuphine experiencing no or mild pain compared with 15% and 25% of patients in the morphine group, respectively.
Outcome metrics
In terms of additional outcome metrics, significantly fewer patients on nalbuphine requested rescue medication compared with those on morphine (59% vs. 41%; P = 0.009), demonstrating the effectiveness of nalbuphine in pain management. Furthermore, the discharge rates from the emergency room were significantly higher for nalbuphine patients (70% vs. 46%; P = 0.0003).
Secondary outcome safety profiles
The secondary outcome analysis involved 89 patients for acute chest syndrome and 179 patients for ICU admission. The results showed that 47 and 93 patients treated with morphine and 42 and 86 patients treated with nalbuphine experienced acute chest syndrome and ICU admission, respectively, with no statistical difference between both treatment (for both outcomes, P > 0.05) [Table 4] [Figure 4].
Table 4.
Safety profiles comparative analysis
| Outcome | Morphine | Nalbuphine | Total | P |
|---|---|---|---|---|
| ACS | 47 | 42 | 89 | 0.54876 |
| ICU admission | 93 | 86 | 179 | 0.52594 |
ACS – Acute chest syndrome; ICU – Intensive care unit
Figure 4.
Secondary outcome safety profiles. ICU – Intensive care unit
DISCUSSION
SCD is a chronic disease with recurrent ED visits due to VOC.[9,10] Due to the chronicity of the disease, long-term exposure to opioids is anticipated. This study presents a balanced statistical background for comparison between the morphine group and the nalbuphine group, 51.43% and 48.57%, respectively. A significant concern of clinicians is to control the pain effectively with the lowest possible side effects, specifically the patient’s tolerance and respiratory effects. Another concern is to control the pain faster and to discharge the patient earlier to maintain the integrity of the healthcare system. The results of this study showed that nalbuphine can be a reliable substitute for morphine. Its efficacy in reducing VOC pain is comparable to morphine, with a marginally better safety profile.
The use of opioids has always been a concern for clinicians, especially in patients with chronic pain. Morphine is a commonly used opioid for the treatment of severe pain. However, because of its respiratory effect and patient dependence, there is a need for alternatives. Nalbuphine has been used to treat severe pain, and in a recent prospective observational study that included pediatric oncology patients, it was found to have a comparable analgesic effect and result in fewer respiratory complications than morphine.[11] In addition, the study found that there was no tolerance in the nalbuphine group, and patients did not require dose escalation later. However, there was clinically significant pain relief on the second day of admission in the morphine group in comparison to the nalbuphine group. This result contradicts our results regarding the analgesic effect of nalbuphine 24 hours post-administration, which was found to be significantly more effective than morphine.
In our paper, VAS was taken from patients 1-h and 6-h post-administration, and, if admitted, at 24 hours. The result showed better pain control in the nalbuphine group at 6- and 24-h post-administration and an insignificant difference at 1 hour. This result indicates a better analgesic effect in the nalbuphine group, especially at later times, which could lead to fewer ED revisits by discharged patients. Although a meta-analysis by Zeng et al. did not find a significant difference in pain control between nalbuphine and morphine, it is essential to note the heterogeneity of the study. Additionally, no studies on using nalbuphine in SCD patients were included in the meta-analysis, and most of the studies were done in perioperative patients.[12]
Significantly more patients in the nalbuphine group reached the desired analgesic effect and were discharged from the ED compared with the morphine group. Decreasing ED length of stay is an essential outcome in patient satisfaction and could reduce the burden on the healthcare system. In the literature review, the only study we found on nalbuphine use in SCD patients was done in the pediatric population by Buchanan et al. However, they did not report an improvement in pain scores in this population.[6] The same study found that the hospital length of stay was higher in the morphine group; however, it was statistically insignificant.
This is the first published paper that assesses the need for rescue medication to control VOC pain. Rescue medication is defined as another dose of opioid needed to control the pain 30 min after receiving the first dose of morphine or nalbuphine, restricted to be repeated two times. Patients who received rescue medications are observed for 6 hours after the last dose of the rescue medication, then if improvement is not noted, they are admitted. It was observed that patients who received nalbuphine were 18% less likely to request another dose of opioids to relieve the pain, which was statistically significant. The result indicates better pain control in the nalbuphine group. This can partially be attributed to the development of tolerance in this population after prolonged exposure to morphine during their lifetime. This result is similar to that of Kubica-Cielińska et al., who found no dose escalation was required in the nalbuphine group.[11]
Respiratory complications in SCD patients are multifactorial and cannot be attributed soley to the opioid effect. A well-known respiratory complication of SCD is ACS, leading to significant morbidity and mortality.[13] Hypoventilation and hypoxia are the triggers for sickling events; both can be caused by opioid analgesia given to VOC patients. Hence, the concerns of opioids in SCD presented with VOC, although they are part of the management of ACS events. Nalbuphine is a unique opioid analgesia that has a lesser effect on the respiratory drive compared to morphine.[14] Among 89 patients diagnosed with ACS, 47 and 42 patients had been treated with morphine and nalbuphine, respectively, thereby highlighting the similarity in ACS complications with both medications. Buchanan et al., in 2005, found that nalbuphine had a lower rate of ACS and shorter hospital length of stay compared to morphine when given to VOC pediatric patients.[6] Another study on the efficacy of nalbuphine compared to morphine on pediatric oncological patients found that the nalbuphine group had a lower incidence of respiratory compromise.[11]
ICU admission is another important outcome studied in this paper. ICU admission is associated with more burden in the healthcare system, and for patient-related effects, it is associated with more nosocomial infections, adverse psychological effects, and higher costs. Avoiding ICU admission is a significant concern for SCD patients admitted for VOC. This study found that while more patients in the morphine group were admitted to the ICU compared to the nalbuphine group, the difference was statistically insignificant.
To our knowledge, our study is the first to compare the use of nalbuphine to morphine in adult SCD patients who presented with VOC. The population is indeed severe SCD patients, evidenced by the presence of SCD complications, history of blood transfusion, the number of ED visits per year, the number of ICU admissions, and laboratory variables [Tables 1 and 2]. Results showed the superior effectiveness of nalbuphine in this population in controlling pain without a significant difference in safety profile compared to morphine.
Limitations
This study is a chart review with its inherent limitations, including missing and inaccurate data, which resulted in the loss of many patients. Second, the nature of chart review studies may have resulted in the possibility of selection bias, despite a clear inclusion and exclusion criteria. Another limitation is that some of the patients might receive non-opioid medications as adjunctive treatment, which is a confounding factor that may affect the outcome. The lack of prior analgesic data (e.g., home medication) may have impacted on opioid tolerance assessment, as baseline exposure could influence pain response; however, such data were not available in hospital records. In addition, some patients in the nalbuphine group received the maximum dose compared to the morphine group, which received 0.1 mg/kg; this could result in a higher analgesic effect in the nalbuphine group. However, this did not affect the side effects. Lastly, the side effects of all medications (such as addiction and dyspepsia) were not studied, and future studies should investigate the prevalence of these side effects.
CONCLUSION
This study found that in adult sickle cell disease patients with severe vaso-occlusive crisis, nalbuphine had a better analgesic effect compared with morphine, with no significant difference in safety profile. Therefore, the use of nalbuphine in this population should be considered as one of the alternatives to morphine. A comprehensive prospective study should investigate the development of tolerance in sickle cell disease patients treated with nalbuphine over a longer period.
Ethical considerations
The study was approved by the Research Ethics Committee of King Faisal University (Ref. No: KFU-REC-2024-APR-ETHICS2226; date: April 24, 2024), Hofuf, Saudi Arabia. Requirement for patient consent was waived owing to the study design. The study adhered to the principles of the Declaration of Helsinki, 2013.
Peer review
This article was peer-reviewed by two independent and anonymous reviewers.
Data availability statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Author contributions
Conceptualization: M.A and M. Almulhim; Methodology: M.A and M. Almulhim, Q.A. YA, M. Alassiri, A.A; Data analysis: Q.A. YA, M. Alassiri, and A.A; Writing–original draft preparation: B.A. L.A and L.Alkhunaizi; Writing – review and editing: S.A. and L. Alshahri; Supervision: M.A.
All authors have read and agreed to the published version of the manuscript.
Conflicts of interest
There are no conflicts of interest.
Funding Statement
None.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.