For patients with sickle cell disease (SCD), severe pain is not simply a symptom to be managed after everything else has been addressed. Vaso-occlusive crises entail vessel blockage and oxygen shortage, as well as severe pain. These crises require urgent attention, often hospitalization, yet Black patients with sickle cell disease have long faced barriers to addressing their severe pain episodes. As clinicians learn more about sickle cell and the pain it causes, they are increasingly moving toward individualized, multimodal care that combines medications, non-pharmacologic interventions, and disease-modifying therapies.
Although gene-editing technologies are improving the big picture, implementing standardized and faster emergency department protocols is well within clinicians’ control today.
Here are new approaches and innovations for managing sickle cell pain to consider.
Sickle cell disease is an inherited group of blood disorders caused by abnormal hemoglobin in red blood cells. Under low-oxygen conditions, red blood cells may become rigid and misshapen, obstructing blood flow. Patients commonly experience hemolysis (the premature destruction of red blood cells), tissue ischemia (reduced blood flow and oxygen to tissues and organs), organ damage, and vaso-occlusive crises. The condition disproportionately affects people of African ancestry, including Black Americans.
According to the CDC, more than 90 percent of people in the United States living with SCD identify as non-Hispanic Black or African American. SCD affects about 1 out of every 365 Black or African American births, with about 1 in every 13 Black or African American babies in the United States born with the sickle cell trait. The estimated life expectancy for people with sickle cell disease is shortened by roughly 20 years compared with the average expected.
While opioids are under heightened public scrutiny, they are an important treatment for SCD. When used properly and under a physician’s care, they can effectively treat pain.
Jagdish Khubchandani, MBBS, PhD, MPH, Professor of Public Health at New Mexico State University, said the emergency room is where things get tricky. No patient record is on file to explain past episodes or conditions, and bias is possible. “Having a patient file ready reduces time to treatment onset, as triage is already in place or the process of [an] individualized patient action plan does not have to start from scratch,” he said, noting that different ERs abide by different guidelines about the wait times for treatment, when to use non-IV treatments, and when to shift to patient-controlled options.
A patient may not always be able to go to the same ER or see the same physician in crisis, so they can have vastly different treatment experiences depending on where they are admitted and who is assigned to their care. Believing a patient’s pain is the first place to start. Implementing standardized approaches to integrating physical exams with patient reports to determine treatment approaches can help patients experiencing acute crisis, especially when the pain is too crippling for consistent verbal or written patient reporting.
Nonsteroidal anti-inflammatory drugs (NSAIDs), such as ketorolac and ibuprofen, are commonly incorporated into multimodal treatment because inflammation contributes to sickle cell pain.
However, clinicians should not assume that adding an NSAID will adequately control severe vaso-occlusive pain. Dr. Khubchandani noted that although NSAIDs are commonly used as first-line non-opioid options, “these have not [been] shown to be very effective given the randomized controlled trials we have.”
A recent literature review similarly supports acetaminophen and NSAIDs as components of multimodal analgesia while emphasizing the need for additional evidence around other non-opioid approaches.
Ketamine is one of the more closely studied non-opioid approaches for sickle cell pain. Unlike opioids, which primarily act through opioid receptors, ketamine antagonizes NMDA receptors involved in pain signaling. This makes it particularly interesting for patients experiencing acute and chronic pain. “Ketamine leads to reduction in pain and opioid use in patients, irrespective of age,” Dr. Khubchandani said.
The risk is that ketamine is not an easy substitute for opioids. Dosing requires expertise, and psychiatric effects and hallucinations can occur. This is why some clinicians favor low-dose ketamine combined with other therapies.
For that reason, ketamine is not a universal first-line replacement for opioid therapy.
Lidocaine can influence sodium channels and other pathways involved in pain sensing. Dr. Khubchandani said lidocaine infusions are a pain management alternative with more promising evidence than conventional NSAIDs.
However, systemic lidocaine requires careful monitoring because of its relatively narrow therapeutic index. Earlier research has described only limited experience with lidocaine infusions in SCD, making it an option that is better suited to experienced teams and carefully selected patients than routine use.
Heat, relaxation techniques, distraction, physical therapy, and behavioral interventions can help components of pain that medications alone may not fully treat. Cognitive behavioral therapy (CBT) and other non-pharmacologic approaches are increasingly being studied as part of multimodal SCD pain management.
However, these interventions complement pharmacologic treatment. They should never be a replacement for them, and they are certainly no reason to delay analgesia approaches. Dr. Khubchandani recommended a “careful combination of pharmacologic and non-pharmacologic therapies,” with non-pharmacologic techniques considered simultaneously rather than before or after medication.
Pain management is only one part of SCD treatment. The investigational pyruvate kinase activator etavopivat is part of the expanding treatment landscape. Disease-modifying therapies aim to reduce the frequency and severity of vaso-occlusive events and prevent cumulative organ damage.
For clinicians, acute-care providers should not view recurrent pain crises solely as isolated emergency department events. Frequent crises may signal an opportunity to reassess a patient’s long-term treatment plan with hematology.
The most dramatic development is the emergence of gene-based therapies that can address SCD’s underlying biology.
Casgevy, or exagamglogene autotemcel, became the first FDA-approved treatment using CRISPR/Cas9 genome-editing technology when it was approved in 2023. Clinicians collect a patient’s own blood stem cells and edit them outside the body. CRISPR/Cas9 increases fetal hemoglobin production, which can prevent red blood cells from sickling.
This one-time cellular therapy aims to substantially reduce or eliminate vaso-occlusive events by changing cell function.
In July 2026, the FDA expanded approval to use Casgevy on patients as young as 2 years old.
Another FDA-approved cellular gene therapy, Lyfgenia, uses a lentiviral vector to genetically modify the patient’s blood stem cells so they produce a modified hemoglobin that reduces sickling.
These treatments are not risk-free. Patients require intensive conditioning chemotherapy before the modified stem cells are returned to the bone marrow, and long-term safety monitoring remains important. Lyfgenia carries a boxed warning for hematologic malignancy and requires lifelong monitoring, including a complete blood count at least every six months for a minimum of 15 years.
“Despite all this progress and understanding, I would say some problems are challenging: bias against minority patients, the costs of all these new therapies, the confusion around off-label use of therapies, lack of coordinated care, or physician training and awareness in primary care continue to pose a major burden,” Dr. Khubchandani said.
The immediate priority remains rapid, individualized treatment. Clinicians should review the patient’s pain plan when available, ask what analgesics have already been taken, assess for complications or alternative diagnoses when the presentation is atypical, and avoid allowing assumptions about addiction or drug-seeking behavior to delay appropriate care.
Physicians should also recognize when a patient’s recurrent crises indicate a larger treatment problem. Persistent or frequently recurring pain may warrant hematology referral, review of disease-modifying therapy, pain-specialist involvement, or consideration of newer therapeutic options.
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