Managing Sickle Cell Disease: Modern Pain Strategies and Pharmacologic Advances

Sickle cell disease (SCD) is an inherited hemoglobinopathy impacting approximately 7.7 million people worldwide, characterized by chronic hemolysis, vaso-occlusion, and multi-organ complications.^1,2 SCD is a genetic disorder most commonly affecting, but not exclusive to, individuals of African descent.^3,4 In the US, SCD is highest in the District of Columbia (1 in 437 births), followed by Mississippi (1 in 683), and South Carolina (1 in 771).⁵

SCD causes a variety of complications including severe anemia, recurrent infections, stroke, and, most notably, painful vaso-occlusive crises (VOC), all of which can range in severity.⁴ SCD impacts hemoglobin, which normally has 2 α and 2 β chains. A mutation in the β-globin gene produces hemoglobin S (HbS). When deoxygenated, HbS molecules polymerize into long chains, forming red blood cells into a sickle shape and leading to blood vessel obstruction, which can progress to organ damage.^2,3,6

The pathophysiology of SCD-related pain involves both acute and chronic mechanisms. Sickled erythrocytes obstruct microvasculature, leading to ischemia, inflammation, and acute VOC pain.² Repeated episodes of vascular occlusion contribute to chronic organ damage, central sensitization, and neuropathic pain syndromes that may persist even outside of crisis episodes.² Although current pain management strategies remain essential, the field is evolving rapidly. The FDA recently approved exagamglogene autotemcel (Casgevy; Vertex) and lovotibeglogene autotemcel (Lyfgenia; Bluebird Bio), the first gene-editing and gene addition therapies for SCD, demonstrating promising therapeutic potential and highlighting the pace of innovation in this field.⁷ Although gene therapy is creating new possibilities for preventing SCD–related complications in the future, individuals currently living with SCD continue to face the reality of severe VOC pain, making effective pain management essential.

Outpatient Management: Reducing Crises and Addressing Long-Term Pain

Outpatient care focuses on preventing crises, reducing chronic pain, and improving overall functioning. Hydroxyurea remains the cornerstone of preventive therapy by increasing fetal hemoglobin and reducing VOC frequency.⁴ For patients with recurrent crises despite hydroxyurea, additional agents such as crizanlizumab (Adakveo; Novartis) and L-glutamine have demonstrated reductions in VOC rates and are endorsed by major guidelines for use in select patients.⁸

The American Society of Hematology (ASH) and CDC guidance emphasize the value of psychological and physical therapies for chronic SCD pain.^2,9 Interventions such as cognitive behavioral therapy, mindfulness, relaxation exercises, heat application, and massage help address the biopsychosocial contributors to chronic pain. A Duke University qualitative study found that mindfulness training improved coping, reduced stress, and increased patients’ sense of control over pain.¹⁰ Unfortunately, nonpharmacotherapy strategies alone are rarely sufficient to treat the severe pain experienced during a VOC. Therefore, pharmacotherapy is the mainstay of treatment for these patients.

Pharmacologic outpatient management is often multimodal. Nonsteroidal anti-inflammatory drugs (NSAIDs) remain useful for inflammatory pain when kidney function is adequate.² Neuropathic agents can be appropriate adjuvant treatment. A 2021 phase 2 study found that gabapentin significantly improved worst-pain scores compared with placebo in adults with homozygous hemoglobin SS experiencing VOC pain (adjusted mean reduction in worst-pain score –1.5 vs –0.5; p=0.03), suggesting it may be useful as a component of the SCD analgesic strategy.¹¹

Selective norepinephrine reuptake inhibitors (SNRIs) may also be a helpful adjuvant for patients with chronic neuropathic features. Evidence from a 2014 Cochrane review of 3541 patients found significant improvement in neuropathic pain with duloxetine (Cymbalta; Eli Lilly) compared with placebo (RR for ≥50% pain reduction = 1.73; 95% CI, 1.44-2.08).¹²Although data in SCD-specific populations are limited, ASH guidelines endorse considering SNRIs when neuropathic mechanisms contribute to pain in patients with SCD.²

Although neuropathic agents and NSAIDs provide important support, opioids remain first-line therapy for acute VOC pain due to the severe, ischemic nature of VOC and the limited analgesic potency of non-opioid options.² In outpatient settings, opioids should be prescribed with individualized dosing, careful monitoring, and continuity with a single clinician to reduce fragmentation and improve safety.

Inpatient Management: Treating Severe Vaso-Occlusive Crisis Pain

When pain escalates beyond outpatient control, emergency and inpatient management become necessary. VOC is a medical emergency requiring rapid treatment. Analgesics should ideally be administered within 30 minutes of arrival, as delays are associated with prolonged pain, increased morbidity, higher opioid requirements, and increased hospitalization risk.^8,13,14 Opioids, commonly administered parenterally, are first line for acute VOC because VOC pain is severe, ischemic, and rapidly progressive. Non-opioids provide insufficient analgesia in this context. Hydromorphone and morphine are commonly used rapid-acting opioids and should be titrated frequently according to patient-reported pain.¹⁴

Because many individuals with SCD often have high opioid tolerance due to exposures during previous VOCs, individualized dosing strategies and awareness of opioid tolerance are important. Undertreatment of VOC pain remains a recognized problem, influenced in part by misconceptions about opioid misuse in SCD.^2,8,15 Clinicians should ensure that undertreatment does not occur due to misconceptions surrounding opioid use.^2,13

Patient-controlled analgesia (PCA) can be an effective strategy for managing acute VOC pain in adults and children with SCD.² In a randomized controlled trial of adults with VOC, PCA produced adequate pain relief while resulting in significantly lower total morphine use compared with continuous infusion (median 16 mg/day vs 23 mg/day; p = 0.04).¹⁶ A pediatric retrospective cohort of 87 VOC admissions found that initiating PCA within 48 hours was associated with a shorter time to adequate analgesia (median 41 hours earlier) and reduced hospital length of stay (4.4 vs 5.8 days; p = 0.03).¹⁷ In a pediatric cohort evaluating demand-only PCA for VOC, mean opioid use fell by approximately 73% (from 13.3 mg/kg to 3.6 mg/kg; p < 0.001), hospital length of stay decreased by 2.7 days on average (7.2 to 4.5 days; p < 0.001) and complications were significantly reduced, including acute chest syndrome (21.9% to 2.8%; p = 0.004) and hypoxia (28% to 6.9%; p < 0.001).¹⁸ Although outcomes vary depending on PCA settings and timing of initiation, PCA should be considered as part of the multimodal impatient analgesia approach for VOC.

Although low-dose ketamine can serve as component of a multimodal regimen, a separate clinical scenario arises when patients experience opioid-refractory VOC pain. Targeting N-methyl-D-aspartate (NMDA) receptors with ketamine has been shown to reduce pain signaling, hyperalgesia, and opioid tolerance.²In one prospective cohort study, average intravenous (IV) morphine use decreased from 145.6 mg/day to 112 mg/day (mean reduction 33.6 mg; p=0.04) after ketamine was initiated, while mean pain scores improved from 9.1 to 5.7 (p<0.01).¹⁹ Another report described a similar response when a low-dose ketamine infusion (0.06–0.1 mg/kg/hr) was added for a patient whose VOC pain was not improving with opioids; after about 48 hours, her opioid use dropped by approximately 41%, and her pain score decreased by 2 points.^2,19

Another promising inpatient option is buprenorphine (Brixadi; Braeburn), which provides steady analgesia with less risk of respiratory depression. Patients can transition to buprenorphine in several ways, including standard induction (waiting for natural withdrawal) or microdosing, which allows overlap with full-agonist opioids and helps avoid precipitated withdrawal. Reported strategies in the literature include sublingual doses of 0.5 mg to 2 mg, buccal film 300 mcg to 450 mcg every 12 hours, a 10 mcg/h transdermal patch, and carefully titrated IV doses (0.15–0.3 mg).^13,15,20-21 A 2025 randomized trial in patients on high-dose opioids found that buprenorphine initiation reduced daily opioid requirements by approximately 33% (mean reduction 70 mg morphine equivalents; p<0.001) and improved pain interference scores.²⁰ Observational reports also show that more than 80% of hospitalized patients successfully complete microdosed inductions without precipitated withdrawal and report improved pain control.^15,21

A structured transition plan is essential before discharge to prevent rebound pain and reduce avoidable readmissions. Patients should leave the hospital with a clear home analgesic regimen, tapering plan when appropriate, refills, and follow-up appointments, preferably with an outpatient clinician who can maintain continuity of care. Providing written individualized pain plans and reviewing them verbally with patients before discharge improves pain control and fewer emergency department visits.^22-24

Conclusion

Despite the promise of gene therapies, most individuals with SCD continue to experience recurrent acute pain and chronic high-impact pain that limit functioning and quality of life.^26,27 Effective SCD pain management requires an integrated, multimodal strategy across outpatient and inpatient settings. Outpatient treatment focuses on VOC prevention through therapies such as hydroxyurea, crizanlizumab, and L-glutamine, supported by neuropathic agents, NSAIDs, opioids when needed, and evidence-based nonpharmacologic interventions.^2,4,8 Although direct SCD-specific data for some neuropathic agents are limited, broader evidence supports their use when chronic or neuropathic pain mechanisms are present.²

When VOCs occur, inpatient care must be rapid and aggressive, including timely opioid therapy, demand-only PCA, and multimodal analgesia. Recent data reinforce the roles of both subanesthetic ketamine as an opioid-sparing adjunct and higher-intensity NMDA-directed therapy for opioid-refractory VOC pain.^19,25 Buprenorphine also has demonstrated an emerging role in the treatment of this patient population. Structured transition planning, including personalized pain plans, follow-up arrangements, and thoughtful discharge opioid tapering, remains essential to continuity of care and reducing avoidable readmissions.^22-24

Contemporary understanding recognizes SCD pain as a complex biopsychosocial condition requiring coordinated pharmacologic, psychological, and mechanism-targeted approaches. As therapeutic options evolve, pharmacists remain central to optimizing multimodal pain regimens, addressing undertreatment, supporting transitions of care, and promoting equitable, patient-centered management across all settings.

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