Children with sickle cell disease come to the emergency department (ED) in severe pain more than 70,000 times a year in the United States, and up to 70% of those visits end in a hospital admission. Despite that burden, no approved drug exists that treats the underlying cause of a sickle cell acute pain episode. Arginine, an inexpensive amino acid supplement, looked like one of the most promising candidates in decades. An earlier phase 2 trial found it safe and opioid sparing, with a shorter hospital stay [3]. A large PECARN trial has now put it to the test.
The STArT trial, published in JAMA, randomized 274 children and young adults with sickle cell acute pain episodes to IV arginine versus placebo in addition to IV opioids. The study was halted early because arginine was not shortening the time it took for a pain crisis to resolve.
- The researchers measured the time from the first study infusion to the last dose of IV opioid. This remains an outcome the US Food and Drug Administration (FDA) prefers for new drugs that treat acute sickle cell pain [1].
What happened?
The trial stopped early for futility. Arginine had a similar time-to-crisis resolution result as placebo [1]. At the planned interim analysis in June 2024, after 76% of the target enrollment, there was less than a 6% chance that finishing the study would produce a positive result.
What interesting findings can be gleaned from the existing data?
- Median time to crisis resolution: Arginine (60.8 hours) versus placebo (65.8 hours). The 7.2-hour difference favored arginine, but the confidence interval was wide enough to include a benefit for either group (95% CI, −21.6 to 35.9 hours). Interestingly, the times varied enormously between hospitals, with median times differing by as much as 61 hours from site to site [1,2].
- Everything else we measured: There was no difference in total opioid use, pain scores, hospital length of stay, or patient-reported outcomes at discharge. Children in both groups did feel meaningfully better 7-10 days after they went home.
- Baseline chronic pain: 41% of patients reported chronic sickle cell pain, defined as pain on 15 or more days per month for the previous 6 months.
- Safety: no safety concerns. Serious adverse events were similar in the two groups and no participant died.
Why This Matters
But let’s not close the book on arginine quite yet. The larger story here involves two issues: the criteria the study used to enroll an acute pain episode, and the changing inpatient pain practices in US hospitals.
Inclusion Criteria: Patients entered the study if they arrived at the ED with acute pain attributed to sickle cell disease and needed IV opioids. Nothing in that definition confirms a blocked blood vessel. Enrollment rested on how much pain a child reported, and on a clinician’s decision to treat that pain with an opioid. That matters, because an “acute pain episode” and a “vaso-occlusive episode” are not quite the same thing in sickle cell disease. Not every sickle cell pain episode comes from vaso-occlusion, or blocked blood vessels. Pain can also come from nerve injury, from a nervous system that has grown oversensitive after years of repeated crises, or from muscle and bone. Arginine only addresses the vaso-occlusive pathology. A trial that enrolls every kind of pain will dilute the effect of a drug that treats only one kind [5].
In this STArT trial, 41% of participants had chronic sickle cell pain, which the editorialists call higher than expected for this age group. They read that number as a sign that a substantial share of the enrolled children may have hurt for reasons arginine does not treat [5]. One caveat belongs here. The trial found no difference in time to crisis resolution between participants with and without chronic pain [1]. This is a hypothesis about why a real effect could stay hidden.
Hospital practices in pain management: In the United States, hospital stays for a sickle cell pain episode in general have grown steadily shorter over the past 25 years. They are now relatively brief: the editorial published alongside the trial describes a typical stay of under 72 hours [5]. This STArT trial showed that floor directly: 60% of the children were past their crisis within 72 hours [1]. Admission decisions and opioid management also differed markedly across the 10 sites [1,5]. This leaves little room for a study drug to show a statistically clear benefit. The STArT investigators recalculated the numbers after the trial closed using the observed parameters and reported that to detect the effect size they had originally hoped for, a future trial would need more than 900 patients [1]. For a rare disease, that is not feasible.
Of note, in Nigeria and Egypt, where a hospital stay often runs a week or longer, arginine significantly shortened the time to crisis resolution by more than 24 hours [1].
What Now?
The accompanying JAMA editorial suggests that future trials define a vaso-occlusive episode by objective measures rather than by acute pain alone. Candidates include acute chest syndrome, hypoxemia, acute kidney or liver injury, and a very high LDH with a low platelet count [5]. Pain combined with organ injury can be measured objectively in a way that pain alone cannot [5]. Their closing line is that the STArT trial does not close the chapter on arginine. It changes the question.
Also, the STArT team operationalized a functional, multicenter infrastructure for sickle cell disease research. Trials of sickle cell pain have struggled to recruit and enroll patients [1,4]. STArT randomized 274 children and young adults across 10 hospitals and stayed ahead of its annual targets. The editorialists describe the PECARN setup as a replicable infrastructure that future ED trials can build on [1,5].
Take Home Message
Intravenous arginine did not shorten sickle cell pain crises in children and young adults in one of the largest US trials to test it. The trial stopped early because the chance of reaching a positive result had become very small even if enrollment continued. No new safety problem appeared: side effects and serious events were similar in both groups, and no participant died.
The more useful finding may be the one the trial exposed along the way, and it may have a lasting impact on how future drug trials for acute vaso-occlusive pain in sickle cell disease are designed. With US hospital stays for sickle cell pain now under three days and with wide variation in how each hospital manages that pain, time to crisis resolution may no longer be a practical primary outcome for US trials. The trial investigators and the editorialists are both calling for a conversation with the FDA, the American Society of Hematology, other researchers, and patients about more objective outcome measures [5,6].
Why is this important for patients and caregivers
- Arginine is an inexpensive nutritional supplement that researchers hoped would shorten sickle cell pain crises. This trial randomized 274 children and young adults, 271 of whom received the study infusion, and found that it did not.
- The trial found no new safety problem. Children who received arginine had about the same side effects as children who received the salt water infusion.
- A trial that answers “no” still moves things forward. Researchers now believe this trial may have measured the wrong thing, not that arginine has no role at all. It also showed that sickle cell pain care differs a great deal between hospitals. Both findings may shape how future trials are built.
This blog post is a summary of the following journal publication:
Morris CR, Hatabah D, Korman R, et al. Arginine therapy for sickle cell disease acute pain episodes: the STArT randomized clinical trial. JAMA. Published online August 19, 2026. PMID: 42616542. doi:10.1001/jama.2026.13310
Interested in other PECARN research?
A few related PECARN studies on emergency care for sickle cell pain:
- Opioid Timeliness in the Emergency Department and Hospitalizations for Acute Sickle Cell Pain — Gwarzo et al, JAMA Pediatrics, 2025. Children who received their first opioid dose faster after arriving in the emergency department were less likely to be admitted to the hospital. PMID: 40892426. doi:10.1001/jamapediatrics.2025.2967
- Intranasal fentanyl and discharge from the emergency department among children with sickle cell disease and vaso-occlusive pain — Rees et al, American Journal of Hematology, 2023. Children who got pain medicine through a nasal spray while waiting for an intravenous line were more likely to go home from the emergency department. PMID: 36606705. doi:10.1002/ajh.26837
- Return visit rates after an emergency department discharge for children with sickle cell pain episodes — Coleman et al, Pediatric Blood & Cancer, 2023. A substantial share of children sent home from the emergency department with sickle cell pain came back within days. PMID: 37458568. doi:10.1002/pbc.30553
References
- Morris CR, Hatabah D, Korman R, et al. Arginine therapy for sickle cell disease acute pain episodes: the STArT randomized clinical trial. JAMA. Published online August 19, 2026. PMID: 42616542. doi:10.1001/jama.2026.13310
- Rees CA, Hatabah D, Korman R, et al. Hospital variations in time-to-crisis-resolution among children and adolescents with sickle cell disease. Am J Hematol. 2026;101(1):206-212. PMID: 41190764. doi:10.1002/ajh.70129
- Morris CR, Hatabah D, Korman R, et al. Arginine therapy for pain in sickle cell disease: a phase-2 randomized, placebo-controlled trial. Am J Hematol. 2025;100(7):1119-1131. PMID: 40270092. doi:10.1002/ajh.27692
- Brousseau DC, Scott JP, Badaki-Makun O, et al. A multicenter randomized controlled trial of intravenous magnesium for sickle cell pain crisis in children. Blood. 2015;126(14):1651-1657. PMID: 26232172. doi:10.1182/blood-2015-05-647107
- Anum SJ, Kanter J. Arginine treatment and sickle cell disease pain: a great STArT, but a hard end point. JAMA. Published online August 19, 2026. PMID: 42616535. doi:10.1001/jama.2026.14849
- Morris CR, Ahmad F, Airewele G, et al. Sickle cell disease treatment with arginine therapy (STArT): results of a phase-3 randomized controlled trial. Blood. 2025;146(suppl 1):616. doi:10.1182/blood-2025-616
