Inclusion Criteria:  Age 3-21 years of age, inclusive; AND Established diagnosis of sickle cell disease (any genotype); AND Pain requiring medical care in an acute care setting (ED, hospital ward, day hospital, clinic) not attributable to non-sickle cell causes, treated with parenteral opioids.  Exclusion Criteria:  Responds to 2 doses of IV opioids sufficiently for outpatient management Greater than 12 hours from first dose of intravenous opioids to treat current pain in acute care setting Hemoglobin less than 5 gm/dL or emergent need for red blood cell transfusion for hemodynamically unstable patient; OR Ketamine use in the emergency department for treatment of VOE; OR Glutamine within 30 days; OR New SCD drug use < 3 months (e.g. Hydroxyurea, voxelotor, crizanlizumab, etc) OR Acute mental status or neurological changes; OR Acute stroke or clinical concern for stroke; OR Three or more ED visits for sickle cell related pain receiving parenteral opioids in previous 7 days (not including current ED visit); OR Hospital discharge within previous 7 days; OR Hypotension requiring clinical intervention; hemodynamic instability; septic shock; OR Previous randomization in this arginine phase 3 RCT; OR Use of inhaled nitric oxide, sildenafil or arginine within the last month; OR Non-English or non-Spanish speaking; OR pregnancy; OR Allergy to arginine; OR PI/clinical team concerns for compliance/issues that may adversely impact study participation/outcome; OR Adults 18 years or older who lack medical decision-making capacity to consent