A randomized, placebo-controlled trial of arginine therapy for the treatment of children with sickle cell disease hospitalized with vaso-occlusive pain episodes

Abstract

Painful episodes of vaso-occlusion are the leading cause of hospitalizations and emergency department visits in sickle cell disease, and are associated with increased mortality. Low nitric oxide bioavailability contributes to vasculopathy in sickle cell disease. Since arginine is the obligate substrate for nitric oxide production, and an acute deficiency is associated with pain, we hypothesized that arginine may be a beneficial treatment for pain related to sickle cell disease. Thirty-eight children with sickle cell disease hospitalized for 56 episodes of pain were randomized into this double-blinded placebo-controlled trial. Patients received L-arginine (100 mg/kg tid) or placebo for 5 days or until discharge. A significant reduction in total parenteral opioid use by 54% (1.9 ± 2.0 mg/kg versus 4.1 ± 4.1 mg/kg, P=0.02) and lower pain scores at discharge (1.9 ± 2.4 versus 3.9 ± 2.9, P=0.01) were observed in the treatment arm compared to the placebo one. There was no significant difference in hospital length of stay (4.1 ± 01.8 versus 4.8 ± 2.5 days, P=0.34), although a trend favored the arginine arm, and total opioid use was strongly correlated with the duration of the admission (r=0.86, P<0.0001). No drug-related adverse events were observed. Arginine therapy represents a novel intervention for painful vaso-occlusive episodes. A reduction of narcotic use by >50% is remarkable. Arginine is a safe and inexpensive intervention with narcotic-sparing effects that may be a beneficial adjunct to standard therapy for sickle cell-related pain in children. A large multi-center trial is warranted in order to confirm these observations.

Figures

Figure 1.

CONSORT flow diagram. Of 110 pain events assessed for study participation during years 2000–2007, 57 pain events were randomized into this placebo-controlled trial and 56 received either arginine therapy or placebo per protocol, with 28 events in each arm. Two patients were excluded after randomization into the arginine arm when it was determined that they had received no parenteral opioids throughout their admission, an eligibility criterion. Narcotic records were incomplete for two patients randomized to the placebo arm; these two patients were excluded from the total opioid use analysis only. One patient randomized to the placebo arm received three doses of arginine due to a pharmacy error. A total of five patients were withdrawn from the study and intervention discontinued, however their data were included in the intent-to-treat analysis. The Children’s Hospital & Research Center Oakland admits ~ 160 children with SCD and painful vaso-occlusive events year. Patients enrolled were among a convenience sample recruited weekdays when the study principal investigator (PI) or research nurse was on-site and available to consent for the study, a legal guardian was available to provide consent, and the pharmacy could perform the randomization.

Figure 2.

Impact of arginine therapy on total opioid use (mg/kg) and Pearson’s correlation between total opioid use (mg/kg) and total length of hospital stay (days). (A) Arginine supplementation (unfilled circles) led to a significant and clinically relevant reduction in total opioid use by 54% over the course of the hospital stay compared to total opioid use in the placebo group (filled circles). The difference remains significant even when the two outliers with the largest total opioid use in the placebo arm are excluded from the analysis (P=0.04). (B) Total opioid use (mg/kg) is directly correlated to length of hospital stay (r=0.86, P<0.0001).

Figure 3.

Impact of arginine therapy on pain scores. 10-cm visual analog scale (VAS) pain scores were similar at the time of admission in both groups, but were 2 cm lower at discharge in the arginine group compared to the placebo group (P=0.01).