Arginine Therapy for Vaso-Occlusive Pain Episodes in Sickle Cell Disease.

Vaso-occlusion is the principal factor in the morbidity of sickle cell disease (SCD). Vaso-occlusive painful episodes (VOE) are common, debilitating, and the leading cause of hospitalizations, emergency room visits, and are associated with an increased mortality rate. There is no effective therapy that targets the underlying mechanisms of VOE. Symptomatic relief with analgesics is the only availabel treatment. Nitric oxide (NO) is a potent vasodilator that contributes to a variety of vaso-occlusive events in SCD. We have found that an arginine deficiency and low NO bioavailability occurs during VOE in SCD. Since arginine is the obligate substrate for NO production, and an acute deficiency is associated with VOE, we hypothesized that arginine supplementation may be a safe and beneficial treatment for sickle cell pain.

Hospitalized SCD patients > 3 years diagnosed within 24 hours with VOE and without associated complications were eligible; written informed consent was obtained. A total of 56 patients completed randomization in this double-blinded, placebo controlled trial. A standardized treatment and monitoring program for VOE was followed. Average age was 13.9 ± 4 years (range 3.6-19 years), and 52% were female. Patients received intravenous (IV) or oral arginine (0.1 gram/kg TID, n=28) or placebo (n=28) for 5 days or until discharge from the hospital. Narcotic records for 2 patients (randomized to placebo arm) were incomplete and were not included in the narcotic use analysis. An intention to treat analysis was performed for narcotic use applying an unpaired t-test with Welch's correction to adjust for unequal variance.

Age was equally distributed between treatment and placebo groups. 57% of the arginine treatment group and 46% of the placebo group were female. A significant reduction in narcotic use (defined as total morphine use over the course of the hospital stay in mg/kg) by 56% was observed in the treatment arm receiving IV or oral arginine compared to placebo (mean ± SEM: 1.8 ± 0.4 mg/kg; n=28 vs. 4.1 ± 0.8mg/kg; n=26, p=0.01). Average length of hospitalization was 4.5 ± 0.4 days, and there was no significant difference between the 2 groups (4.1 ± 0.3 vs. 4.8 ± 0.5 days, p = 0.27; arginine vs. placebo arm). Four episodes of acute chest syndrome (ACS) developed during the study, three in the treatment arm and one in the placebo arm. There was one patient who experienced clinical deterioration associated with ACS requiring emergent transfusion and a transfer to the pediatric intensive care unit (PICU) in the placebo arm. No clinical deterioration or PICU transfers occurred in the arginine arm. Five in the treatment arm received transfusion vs. four in the placebo arm. No drug-related adverse events were observed. No significant differences were observed between pre and post therapy liver or renal function, or hematological parameters in the arginine treatment group vs. placebo. Two patients admitted for pain management ultimately did not receive IV narcotics. Both had been randomized into the arginine-treatment arm and received arginine therapy per protocol throughout their hospital stay and required only oral narcotics and non-steroidal analgesia. Reduction in narcotic use in the treatment arm remained significant even when these 2 patients were excluded from the analysis (p=0.02).

IV arginine therapy represents a novel nutritional intervention for the treatment of pain in hospitalized patients with SCD. Use of IV arginine should also be considered in the treatment of VOE in the emergency department setting prior to hospitalization, although further investigation is warranted. A reduction of narcotic use by over 50% observed in this study is remarkable, as this is the first successful intervention for sickle cell-related pain that targets the underlying mechanism of vaso-occlusion through a promising NO-based therapy. Arginine is a safe and inexpensive intervention with narcotic-sparing effects that should be considered as an adjunct to standard therapy for VOE requiring hospitalization.

Off Label Use: Arginine for treatment of sickle cell vaso-occlusive pain episodes.