Sickle Cell Acute Pain Episodes: STArT Trial

A faces pain-assessment sheet and a prepared syringe on an overbed tray table, with an adolescent patient resting on the stretcher behind, in a pediatric emergency department

Article reviewed: 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
DOI: 10.1001/jama.2026.13310 | PubMed: PMID 42616542

A child with sickle cell disease arrives in your emergency department (ED) in an acute pain episode. In one of the largest US pediatric trials of a treatment for acute sickle cell pain, how long that crisis lasted varied far more between hospitals than it did between the study drug and placebo.

The PECARN STArT trial randomized 274 children and young adults with sickle cell acute pain episodes to IV arginine or saline placebo at 10 US children’s hospitals. Arginine, which targets the nitric oxide depletion that drives vaso-occlusion, did not shorten time to crisis resolution, and the trial was halted early for futility [1]. The more useful numbers are in site-level data. Median time to crisis resolution varied by as much as 61 hours between participating hospitals, and mean total parenteral opioid by as much as 3.0 mg/kg of based on morphine-equivalent calculations [1,3]. These are observational site differences. They may reflect analgesia and opioid-discontinuation practice, patient mix, and other institutional factors that the analyses can not distinguish.

Study Design

STArT was a double-blind, placebo-controlled phase 3 randomized clinical trial conducted (2021-2024). Patients aged 3 to 21 years with sickle cell disease who presented to the ED with acute pain requiring parenteral opioids and hospital admission were randomized within 12 hours of their first IV opioid dose. Arginine was given as a 200 mg/kg loading dose followed by 100 mg/kg every 8 hours until discharge. Of 274 patients randomized, 271 received study drug, 129 arginine and 142 placebo. The primary outcome was time to crisis resolution, the interval from first study drug delivery to the last dose of parenteral opioid, and it is the outcome the US Food and Drug Administration prefers for regulatory approval in this population [1].

Results

Median time to crisis resolution was 60.8 hours with arginine versus 65.8 hours with placebo, an absolute difference of 7.2 hours favoring arginine with a confidence interval spanning benefit in either direction (95% CI, -21.6 to 35.9 hours). Total parenteral opioid use, pain scores, and hospital length of stay were similar between groups, and the arginine effect on time to crisis resolution did not differ significantly by chronic pain status. Serious adverse events did not differ and there were no deaths [1].

Three descriptive findings arose from the collected data:

Site variation. Median time to crisis resolution differed by up to 61 hours across the 10 hospitals, and mean total parenteral opioid by up to 3.0 mg/kg [1,3].
Delay to study drug. Study drug arrived a median of 8 hours after the first ED dose of IV opioid, and only 50.4% of participants had sought care within 24 hours of pain onset [1]. In 23 of 271 treated participants the last IV opioid had already been given before study drug arrived, producing a primary outcome of zero hours.
Chronic pain prevalence. 41% of participants met criteria for chronic sickle cell pain, including 34% of children younger than 12 years [1]. A single triage pain score means something different in a child who already has pain 15 or more days a month.

Build an Expedited Pain Plan in the Emergency Department

It is unclear why the wide variation in time to pain crisis resolution. The study was not designed to untangle the reasons, but in theory the causes are likely multifactorial and include: patient mix, underlying chronic pain, time spent in pain before arrival, institutional practices, and individual practitioner analgesia practices. That last one is something that you can act on today.

An expedited pain plan for a sickle cell acute pain episode

Consider administering intranasal fentanyl at triage, if IV opioids are not readily available.

The American Society of Hematology 2020 recommendation is to assess the patient and administer analgesia within 1 hour of ED arrival, with reassessment every 30 to 60 minutes. It is a strong recommendation on low-certainty evidence [8].

Two cross-sectional PECARN studies describe what meeting those targets looks like. In a PECARN Registry analysis of 9233 ED visits for uncomplicated sickle cell pain at 12 children’s hospitals, a first opioid dose within 60 minutes of arrival was associated with lower odds of hospitalization (OR 0.84; 95% CI, 0.75-0.95). That association held even when the second dose fell outside 30 minutes (OR 0.85), and with a timely first dose the odds fell stepwise as the second-dose interval shortened: 0.78 within 60 minutes, 0.70 within 45, and 0.62 within 30 (95% CI, 0.52-0.75) [9]. Separately, among 400 children at 20 academic pediatric EDs in the US and Canada, only 19% received intranasal fentanyl, and those who did had nearly ninefold higher adjusted odds of discharge from the ED (adjusted OR 8.99; 95% CI, 2.81-30.56; P < .001) [10].

Both studies are cross-sectional and neither establishes causality. Timeliness of the first dose is the more robust of the two signals, since it survived a late second dose.

Not All Pain is the Same

The STArT study enrolled acute pain episodes, defined by pain severe enough to need parenteral opioids. However, arginine specifically targets vaso-occlusion pain. The accompanying JAMA editorial argued that these are not the same thing: the term acute pain episode has become operationally synonymous with vaso-occlusive episode, yet acute pain in sickle cell disease also arises from neuropathic mechanisms, central sensitization, and musculoskeletal injury [2]. A trial that heterogeneously enrolls all of them dilutes the study population. Notably, 41% of the study participants had underlying chronic pain [1].

Can We Narrow the Patient Inclusion Criteria?

The editorial accompanying STArT argues for enrolling a more narrow subset of patients, focusing on objective markers rather than pain severity [2]:

Hypoxemia, worrisome for acute chest syndrome
Very high LDH with thrombocytopenia, reported in a small retrospective adult series as suggesting a severe vaso-occlusive subtype that prompted consideration of early intervention [6]
Acute kidney injury or acute liver injury, used the way organ dysfunction defines severity in sepsis trials

Trial design sidebar

Why the trial stopped early, and why that matters beyond arginine

STArT closed after 76.1% of target enrollment because conditional power for the primary outcome had fallen below 6%, even assuming the full 17-hour effect originally hypothesized. Futility stopping is not a safety signal, and it is not proof of no effect. It means the predicted chance of reaching the primary statistical result was low if enrollment continued, not zero [1].

The primary outcome measure is a possible culprit. Time to crisis resolution correlated with hospital length of stay, which can be shaped as much by institutional opioid discontinuation practice as by drug biology [1,2,7]. US stays have trended shorter over the last 25 years and are now brief: the editorial describes a contemporary median under 72 hours, and PECARN’s MAGiC trial reported a median under 56 hours [1,2,5]. A post hoc recalculation using STArT’s own variance estimates put the required sample size above 900 participants [1]. Morris et al note that phase 3 trials targeting acute sickle cell pain have so far failed to shorten either hospital length of stay or time to crisis resolution [1], despite the study drugs spanning four largely distinct mechanisms: inhaled nitric oxide in 2011 [11], IV magnesium in PECARN’s MAGiC trial in 2015[5], poloxamer 188 in 2021 [12], and rivipansel, an E-selectin antagonist, in 2023 [13]. Arginine is the fifth agent to move nothing on this family of endpoints. The authors now question the outcome measure itself.

Three levers are on the table. The first is to enroll patients with objective organ injury, where the endpoint can be adjudicated on an image or a laboratory value rather than on a clinician’s decision to stop an opioid infusion. Among 54 STArT participants who either had acute chest syndrome at presentation or developed it after randomization, mean time to crisis resolution was 108 hours with arginine versus 184 hours with placebo (29 vs 25 participants; P = 0.16; median difference 34 hours) [4]. Because acute chest syndrome status partly arose after randomization, this exploratory comparison cannot establish a treatment effect. The editorialists note that further detail from this cohort is awaited and would likely be informative [2]. The second is to change the outcome entirely. STArT captured 72-hour and 28-day ED return and rehospitalization as safety outcomes, and the editorialists argue these belong on the efficacy side, because the burden of sickle cell disease acute pain “may reside less in the duration of individual hospitalizations and more in the frequency of readmissions and ED revisits” [2]. The 28-day ED-return rates were 27.1% with arginine and 32.4% with placebo, and at a disease level return visits follow as many as 29% of initial ED encounters, with up to 28% of hospitalized children readmitted within 30 days [1]. The third lever is the design itself: the editorialists raise external control cohorts, or a crossover in which patients serve as their own controls, as ways to cut the participant numbers a conventional trial would need [2].

Bottom Line

Arginine is not ready. Nothing in this STArT trial displaces supportive care, NSAIDs, and opioids for a sickle cell acute pain episode.
The 61-hour spread between hospitals was more than three times the trial’s originally hypothesized 17-hour treatment difference. How your department assesses and treats pain is part of what that spread reflects.
The American Society of Hematology recommends giving an analgesic dose within the first hour of ED arrival. Consider intranasal fentanyl at triage, while awaiting IV access.

References

Morris CR, Hatabah D, Korman R, et al; Pediatric Emergency Care Applied Research Network (PECARN). 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
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
Rees CA, Hatabah D, Korman R, et al; PECARN. 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, 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
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
Gardner K, Thein SL. Super-elevated LDH and thrombocytopenia are markers of a severe subtype of vaso-occlusive crisis in sickle cell disease. Am J Hematol. 2015;90(10):E206-E207. PMID: 26205137. doi:10.1002/ajh.24126
Ataga KI. The challenge of clinical end points in sickle cell disease. Blood. 2023;142(24):2047-2054. PMID: 37890140. doi:10.1182/blood.2023021220
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. PMID: 32559294. doi:10.1182/bloodadvances.2020001851
Gwarzo I, Coleman KD, McKinley K, et al. Opioid timeliness in the emergency department and hospitalizations for acute sickle cell pain. JAMA Pediatr. 2025;179(11):1194-1202. PMID: 40892426. doi:10.1001/jamapediatrics.2025.2967
Rees CA, Brousseau DC, Ahmad FA, et al; SCD Arginine Study Group and PECARN. Intranasal fentanyl and discharge from the emergency department among children with sickle cell disease and vaso-occlusive pain: a multicenter pediatric emergency medicine perspective. Am J Hematol. 2023;98(4):620-627. PMID: 36606705. doi:10.1002/ajh.26837
Gladwin MT, Kato GJ, Weiner D, et al; DeNOVO Investigators. Nitric oxide for inhalation in the acute treatment of sickle cell pain crisis: a randomized controlled trial. JAMA. 2011;305(9):893-902. PMID: 21364138. doi:10.1001/jama.2011.235
Casella JF, Barton BA, Kanter J, et al. Effect of poloxamer 188 vs placebo on painful vaso-occlusive episodes in children and adults with sickle cell disease: a randomized clinical trial. JAMA. 2021;325(15):1513-1523. PMID: 33877274. doi:10.1001/jama.2021.3414
Dampier CD, Telen MJ, Wun T, et al; RESET Investigators. A randomized clinical trial of the efficacy and safety of rivipansel for sickle cell vaso-occlusive crisis. Blood. 2023;141(2):168-179. PMID: 35981565. doi:10.1182/blood.2022015797