Abstract: We included five randomized placebo-controlled studies with a total of 386 participants (aged three to 53 years). Of these, two shorter parallel studies (n = 306) compared intravenous magnesium sulphate to placebo (normal saline) for admission to hospital due to a vaso-occlusive crisis, for which we were able to analyse data. The quality of evidence was moderate for studies in this comparison, mainly due to limitations due to risk of bias and imprecision. Two of the three longer-term studies comparing oral magnesium pidolate to placebo had a cross-over design. The third was a parallel factorial study which compared hydroxyurea and oral magnesium to each other and to placebo over a longer period of time; we only present the comparison of oral magnesium to placebo from this study. The quality of evidence was very low with uncertainty of the estimation. The eight-hourly dose levels in the two studies of intravenous magnesium were different; one used 100 mg/kg while the second used 40 mg/kg. Only one of these studies (n = 104) reported the mean daily pain score while hospitalised (a non-significant difference between groups, moderate quality evidence). The second study (n = 202) reported a number of child- and parent-reported quality of life scores. None of the scores showed any difference between treatment groups (low quality evidence). Data from one study (n = 106) showed no difference in length of stay in hospital between groups (low quality evidence). Both studies reported on adverse events, but not defined by severity as we had planned. One study showed significantly more participants receiving intravenous magnesium experienced warmth at infusion site compared to placebo; there were no differences between groups for other adverse events (low quality evidence). Three studies (n = 80) compared oral magnesium pidolate to placebo. None of them reported data which we were able to analyse. One study (n = 24) reported on the number of painful days and stated there was no difference between two groups (low quality evidence). None of the studies reported on quality of life or length of hospital stay. Two studies (n = 68) reported there were no differences in levels of magnesium in either plasma or red blood cells (moderate quality evidence). Two studies (n = 56) reported adverse events. One reported episodes of mild diarrhoea and headache, all of which resolved without stopping treatment. The second study reported adverse events as gastrointestinal disorders, headache or migraine, upper respiratory infections and rash; which were all evenly distributed across treatment groups (moderate quality evidence). Moderate to low quality evidence showed neither intravenous magnesium and oral magnesium therapy has an effect on reducing painful crisis, length of hospital stay and changing quality of life in treating sickle cell disease. Therefore, no definitive conclusions can be made regarding its clinical benefit. Further randomized controlled studies, perhaps multicentre, are necessary to establish whether intravenous and oral magnesium therapies have any effect on improving the health of people with sickle cell disease.

Plain-language summary: The review included five studies with a total of 386 people with sickle cell disease aged between four and 53 years. Two studies (306 people) compared intravenous magnesium to a placebo (in this case saline (salty water)) in people admitted to hospital as an emergency because of pain and lasted until they were discharged (less than four weeks). Two of the three longer-term studies compared oral magnesium pidolate with placebo and the third study compared hydroxyurea and magnesium pidolate to each other and to placebo but we have only included the results of the comparison of magnesium pidolate to placebo). Not all the studies reported on our outcomes and we could not analyse data from most of the studies. We did find that in the people admitted to hospital as emergency cases, intravenous magnesium did not reduce pain levels, could not shorten the length of time spent in hospital and did not improve their quality of life compared to placebo. However, more people given magnesium experienced warmth where the needle was inserted than those people who were given placebo. Oral magnesium pidolate, given over a longer period, did not reduce the severity of painful episodes and had no measurable effect on properties of sickled red cells (e.g. magnesium levels in the blood). Oral magnesium appeared to be safe and well-tolerated with only mild side effects (diarrhoea and headache). Further research is needed to compare the short-term and long-term benefits of magnesium treatment and its side effects. The quality of evidence for intravenous magnesium and oral magnesium in treating sickle cell disease was moderate for pain when using short-term intravenous magnesium and for levels of magnesium in the blood when taking longer-term oral magnesium supplements. The quality of evidence was low for all other outcomes we measured. All of the included studies of oral or intravenous magnesium for treating sickle cell disease had some aspects that could undermine the reliability of their results. Therefore, we have some uncertainty of these findings and further research may provide evidence that could change our conclusions.