Oral L-Glutamine Powder Lowers Frequency of Sickle Cell–Related Pain Episodes

Oral L-glutamine powder, with or without hydroxyurea, reduced the number of pain events experienced by children and adults with sickle cell disease (SCD), compared with those who received placebo, according to results from a phase III study published in the New England Journal of Medicine.

Oxidative stress can contribute to the complex pathophysiology of SCD, the authors, led by Yutaka Niihara, MD, MPH, professor of medicine at David Geffen School of Medicine at the University of California, Los Angeles, explained. In previous trials, treatment with L-glutamine powder “has been shown to increase the proportion of the reduced form of nicotinamide adenine dinucleotides in sickle cell erythrocytes, which probably reduces oxidative stress and could result in fewer episodes of sickle cell–related pain.”

In the multicenter, randomized, placebo-controlled trial, researchers enrolled 230 patients who were ≥5 years old, had experienced two or more pain crises within the previous year, and were receiving hydroxyurea at a stable dose for at least three months prior to enrollment.

The researchers randomized patients 2:1 to receive either:

  • pharmaceutical-grade L-glutamine powder (n=152)
  • placebo powder (n=78)

Patients received L-glutamine powder 0.3 g/kg twice daily for a total of 48 weeks. Therapy was then tapered for three weeks, followed by a two-week observation period, for a total trial duration of 53 weeks.

The primary efficacy endpoint was the number of pain crises during the 48-week treatment period. For the purposes of their study, the researchers defined a pain crisis as any pain resulting in treatment with parenterally administered narcotic or ketorolac therapy in the emergency department, in an outpatient treatment center, or during hospitalization.

Secondary efficacy endpoints included the number of hospital admissions for sickle cell–related pain, hematologic changes (including hemoglobin and hematocrit levels and reticulocyte count) from baseline to 48 weeks, and the number of visits to the emergency department or outpatient treatment center for sickle cell–related pain.

During the 48-week trial period, patients in the L-glutamine group experienced significantly fewer pain crises compared with those in the placebo group (median = 3 [range = 0-15] vs. 4 [range = 0-15]; p=0.005). This translated to a 25-percent reduction in the number of sickle cell–related pain crises, compared with placebo, during the 48-week treatment period.

L-glutamine also was associated with a lower median number of hospitalizations for sickle cell–related pain and other secondary endpoints (TABLE).

Participants treated with L-glutamine had a longer time to first pain crisis and a longer time between first and second pain crises, compared with those treated with placebo:

  • median number of days to first pain crisis: 84 (range = 62-109 days) vs. 54 (range = 31-73 days; p=0.02)
  • median number of days to second pain crisis: 212 (range = 153-250 days) vs. 133 (range = 115-179 days; p=0.03)

“The time to the first pain crisis began to diverge within two weeks [of treatment start], with sustained separation of curves over the duration of the trial,” the authors noted.

However, no differences were observed between either group in the number of visits to the emergency department that did not result in hospitalization (p=0.09).

All-grade adverse events (AEs) and serious AEs occurred more frequently in the placebo group than the L-glutamine group (100% vs. 98% and 87.1% vs. 78.2%, respectively; p values not reported). However, the following AEs were more frequently reported in the L-glutamine group: low-grade nausea, fatigue, noncardiac chest pain, and musculoskeletal pain (p values not reported). Two patients died during treatment with L-glutamine, but the authors noted that both of these patients presented with a prolonged history of organ failure and additional co-existing medical conditions that may have contributed to mortality.

The benefits of oral L-glutamine powder were seen regardless of hydroxyurea use, the authors reported, with a consistent treatment effect across subgroups; the rate ratio (i.e., the ratio of the recurrent event rates in each trial group) was 0.77 for participants with prior hydroxyurea use and 0.78 for those without hydroxyurea use (p value not reported).

These findings also suggest that the effect of L-glutamine may be additive to hydroxyurea therapy, the researchers concluded, “to lower the incidence of pain crises for those who may have suboptimal response to hydroxyurea.”

The results from this phase III trial supported the U.S. Food and Drug Administration’s approval of oral L-glutamine powder to reduce the acute complications of SCD in children and adults. However, the authors noted that, because the maximum age of trial participants was 58 years, the findings may not be generalizable to older patients with SCD. The study also was not designed to assess long-term benefits or side effects to L-glutamine therapy.

The authors report financial relationships with Emmaus Medical, which funded the study.


Niihara Y, Miller ST, Kanter J, et al. A phase 3 trial of L-glutamine in sickle cell disease. N Engl J Med. 2018;379:226-35.