Magnesium, a treatment for leg cramps?

Leg cramps are reported in up to 60% of adults and 7% of children.¹ They are troublesome and can cause severe pain and sleep disturbance,² and residual pain sometimes occurs in the affected muscles after cramping.³ Up to 20% of people who complain of leg cramps have symptoms every day which are severe enough to require medical intervention.¹ Currently no treatments for leg cramps are proven to be safe and effective¹ but there is a clear need for treatment options.

Quinine has been commonly used to treat leg cramps but TGA approval for this indication was withdrawn in 2004 after reports of an increased risk of thrombocytopenia and four associated fatalities in Australia.⁴

Since magnesium plays a role in neuromuscular transmission and muscle contraction, it has been hypothesised that magnesium deficiency may predispose to muscle cramps.^2,5 Thus magnesium supplements are often recommended to prevent cramps. Does the evidence support using magnesium for this indication?

• Differentiating leg cramp from other conditions can be challenging, the term ‘cramp’ can be used to describe a variety of pain types.
  
• When taking a medical history, consider factors which may account for leg cramp (peripheral vascular disease or motor neurone disease) as well as drug causes (calcium-channel blockers, angiotensin II-receptor antagonists and diuretics).
  
• While magnesium deficiency has been proposed as a cause of leg cramps, there is no evidence that magnesium supplements provide a clinical benefit other than for pregnancy-related leg cramp.
  
• Consider the potential for development of hypermagnesaemia in patients taking magnesium supplements, especially in older people and people with kidney disease.
  
• Magnesium interacts with bisphosphonates and tetracycline antibiotics and should be taken 2 hours before or after these medicines.
  
• Do not prescribe quinine tablets for leg cramps. The efficacy of quinine in preventing cramp is limited and is outweighed by the risk of severe thrombocytopenia, which may be fatal.
  
• Consider non-pharmacological interventions for cramps such as stretching.
  

Differentiating leg cramps from other conditions in older people can be challenging, the term ‘cramp’ can be used to describe a variety of pain types. Consider other causes such as restless legs syndrome, nocturnal myoclonus, myopathic and neuropathic conditions.³

When taking a patient’s medical history include a review of medicines and medical conditions.¹ Consider other factors which may contribute, such as peripheral vascular disease or motor neurone disease. Possible drug causes of cramp include calcium-channel blockers, angiotensin II-receptor antagonists and diuretics.³ Interestingly, the calcium-channel blockers diltiazem and verapamil have been assessed for the treatment of muscle cramp in older people, however the trials were small and of poor quality.^6,7

Physical examination rarely identifies leg cramps because they are involuntary, unpredictable, and usually occur at night. But findings on examination may indicate a potential underlying medical cause (i.e.peripheral vascular disease).^1,5

There are no routine blood tests recommended for the diagnosis of muscle cramps and there is no proven association with electrolyte abnormalities.⁸

The third trimester of pregnancy is often associated with leg cramps, although it is difficult to differentiate between pregnancy as the primary cause and venous insufficiency.⁹ Despite the high incidence of leg cramps in pregnancy, there has been minimal research in this area.

Treatment with quinine was common until its withdrawal as an indication in 2004. The withdrawal was a consequence of 198 reports of thrombocytopenia associated with quinine use (since 1972), including four deaths.⁴ Quinine was withdrawn at a similar time in the US and subsequently, in 2006, the US FDA Federal Register alerted consumers to the problems surrounding off-label use, reporting 665 serious adverse events including 93 deaths since 1969.¹⁰ Despite this, off-label use still continues both here⁴ and overseas.

Evidence is lacking except for pregnancy-associated cramps

The effectiveness and safety of magnesium has been established for eclampsia and pre-eclampsia, arrhythmia, severe asthma, and migraine.¹¹ There is some evidence for efficacy of magnesium supplementation in treatment of leg cramps in pregnant women but not for other people.^2,12

A recent systematic review evaluated the effect of magnesium versus placebo for the treatment of nocturnal leg cramps and found the overall effect of magnesium to be insignificant.² Seven trials were included, one assessed magnesium infusion versus placebo and the rest assessed oral magnesium therapy but dose and frequency of therapy varied between all studies.

A sub-analysis of three of the studies involving only pregnant women showed a significant difference between the magnesium and placebo groups in the median number of leg cramps experienced per week.² However the studies only contained a small number of participants (n=361 in total and n=198 in the subgroup analysis), and therefore was underpowered to detect meaningful differences between groups. In addition selection bias may have impacted results as participants were included in the analysis whose leg complaints may have been confused with disorders not known to be associated with magnesium deficiency (ie, restless leg syndrome).

Another recent systematic review evaluated a further seven studies in patients with leg cramp treated with magnesium.¹² The elemental magnesium dose given varied between studies. The populations included 322 mostly older patients and 202 women with pregnancy-associated leg cramps. After four weeks of treatment, differences in percentage change from baseline of cramps per week between magnesium and placebo groups were small and not statistically significant.

The authors concluded that magnesium is unlikely to provide a meaningful benefit in reducing the frequency or severity of idiopathic leg cramps in older people.¹² The second review also included three further studies on pregnant women; while a meta-analysis was not possible with these, results from the individual studies were considered and found to be mixed. One study found magnesium reduced cramp frequency and pain while the other two found no benefit.¹² Although two of the studies were similar in design and setting,^13,14 their outcomes were different; this may have been because one of the studies lacked baseline measurement of cramp frequency. If cramp frequency before intervention was not comparable between participants in these studies, it is not appropriate to compare the number of cramps experienced during the treatment period.

Oral magnesium supplementation is well tolerated

Both meta-analyses found that magnesium is well tolerated with the most frequent adverse effects affecting the gastrointestinal system (diarrhoea, nausea, vomiting, flatulence and constipation).^2,12

Moderate-to-severe and symptomatic hypermagnesaemia is usually due to excessive supplemental intake of magnesium (eg, as antacids, enemas or by intravenous infusion), most often in patients with kidney impairment. Be aware of the most common clinical features of moderate-to-severe hypermagnesaemia which are usually neuromuscular (eg, loss of deep tendon reflexes, muscle paralysis, depressed conscious state and respiratory depression). Other signs include anorexia, nausea, skin flushing, hypotension, bradycardia/heart block and cardiac arrest.¹⁵

When considering magnesium supplements, ensure patients take a product containing magnesium only. Some magnesium supplements are combined with potassium and may contribute to hyperkalaemia in people taking ACE inhibitors or other medicines which cause potassium retention.³ Consider assessing kidney function in people using medicines that may impair or adversely affect kidney function¹⁶ and watch for signs of toxicity.¹⁵

Small studies have shown some benefit from other medications including diltiazem, gabapentin and vitamin B complex but none can be recommended for muscle cramps because of the poor quality of evidence.^6,17-19 Multivitamins and sodium supplementation have also shown benefit in preventing cramps in pregnant women, although consider the potential risk of hypertension with sodium supplementation.⁹ Australian guidelines recommend calcium supplements for leg cramps in pregnant women based on case reports but also highlight there are no controlled trials to support its use.²⁰ Paracetamol may be useful to manage residual muscle pain after cramping.³

Non-pharmacological therapy

Passive stretch and massage of the affected muscle may relieve cramp and stretching the calf muscles daily has been recommended to prevent cramp.²¹ Although there is no clinical trial evidence to support these measures, anecdotal evidence suggests they may be effective and the risk of adverse effects is low.

Magnesium interacts with other medicines

• Magnesium significantly reduces the absorption of oral bisphosphonates and tetracycline antibiotics and may reduce their activity.
  
• Advise patients to ensure they take these medicines at least 2 hours before or after taking a magnesium supplement.²²