Original Research

Magnesium for the Treatment of Nocturnal Leg Cramps A Crossover Randomized Trial

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BACKGROUND: Nocturnal leg cramps are a common health problem in the ambulatory setting. Our objective was to evaluate the efficacy of magnesium in the treatment of nocturnal leg cramps.

METHODS: Our study was a crossover randomized double-blind placebo-controlled trial. We included patients from a large university-based ambulatory clinic in Buenos Aires, Argentina, with at least 6 cramps during the previous month. A total of 93 subjects took part in a 4-week washout period with placebo. Those who were still eligible (n = 45) were randomized to receive either (1) an oral dose of 900 mg magnesium citrate twice daily for 1 month, followed by a matching placebo for 1 month, or (2) the placebo first, followed by magnesium. Both groups had a 4-week washout period with placebo between each treatment month. Forty-two patients completed the 4-month study. The main outcome was the number of nocturnal leg cramps, and the secondary outcomes were duration, severity, and sleep disorders caused by those cramps.

RESULTS: There were no significant differences between magnesium and placebo in any of the evaluated outcomes. The mean number of cramps was 11.1 (standard deviation [SD] ± 7.3) for placebo versus 11.8 (SD ± 7.6) for magnesium (P = .59). We observed a significant period-effect bias: All patients improved over time regardless of the treatment sequence they received.

CONCLUSIONS: Magnesium was not effective for the treatment of nocturnal leg cramps. The period-effect bias probably occurred because of a combination of the natural history of this condition, a regression to the mean, and a true placebo effect.

Nocturnal leg cramps are a common health problem. The elderly are often affected; in one survey, 70% of the people older than 50 years had experienced at least one cramp in their lives.1 Different treatments have been proposed to relieve nocturnal leg cramps, including stretching, massage, or walking,2 and many pharmacologic interventions have been suggested, such as diphenhidranymine, verapamil,3 vitamin E,4,5 or quinine sulfate.6-10

Quinine sulfate has been prescribed for decades for the treatment of nocturnal leg cramps, but clinical trials have only recently been performed. This is the only drug that has shown efficacy for this problem.3,6,7,9,21 Given the risks of serious side effects, this treatment has to be carefully evaluated to weigh the benefits against potential risks, such as cinchonism (nausea, vomiting, tinnitus, and deafness),11 thrombocytopenia,12 and visual impairment.13 Magnesium plays a central role in metabolism and muscle function by participating in many of the biochemical reactions that take place in the body, particularly in those processes involving the formation and use of adenosin triphosphate (ATP).14 Approximately two thirds of all enzymatic reactions in the body requiring metals as co-factors and all enzymatic reactions that involve ATP require magnesium.15

In pharmacologic doses, magnesium has a curariform action on the neuromuscular junction. It interferes with the release of acetylcholine from motor nerve terminals. Magnesium depletion leads to increased neuronal excitability and enhanced neuromuscular transmission16 with symptoms that include muscle tremor, ataxia, tetany, and cramps.17

Although magnesium therapy has shown positive results for the treatment of nocturnal leg cramps in pregnant women,18 the elderly,19 and patients with type 1 diabetes,20 only the study performed on pregnant women was a double-blind randomized controlled clinical trial. Despite the lack of strong evidence, the use of magnesium salts to relieve nocturnal leg cramps is a common practice in some countries in Europe and Latin America. In addition, magnesium is a safe and affordable drug.


We instructed family physicians at a large university-based ambulatory clinic to refer patients with nocturnal leg cramps for admission to the study. To increase recruitment, we delivered information about this study to all patients visiting the clinic.

We conducted a double-blind placebo-controlled crossover randomized trial. Cramps were defined as painful involuntary skeletal muscle contractions that occurred in the thigh, foot, or lower part of the leg when the patient was in bed or resting.

The entry criteria were: men and women presenting with 6 or more cramps in the previous month; experiencing the same number of cramps after a 4-week of washout period with placebo; aged older than 18 years; normal neurologic examination results of both legs; and a signed informed consent form. The exclusion criteria were: alcohol abuse; psychiatric diseases; terminal disease; type 1 diabetes mellitus; renal failure; pregnancy; arteriopathy or neuropathy of one or both legs; hypocalcemia, hyponatremia, or hypokalemia; not speaking Spanish or not having a telephone; inability to stop taking medications that contained magnesium; and low compliance or having less than 6 cramps after the first washout.

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