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Quinine Risks Limit Muscle Cramp Options, AAN Review Finds

Physicians treating patients suffering from muscle cramps can offer little in the way of pharmaceutical or therapeutic help, and they should avoid using off-label options, especially quinine sulfate and its derivatives, according to a review of prospective studies published in the medical literature over the last 50 years.

The AAN Therapeutics and Technology Assessment Subcommittee reviewed all relevant articles published between 1950 and 2008, and published their findings in the Feb. 23 Neurology.

Panel member Yuen T. So, MD, PhD, professor of neurology and neurological sciences, and director of neurology clinics at Stanford University School of Medicine in Stanford, CA, discussed the subcommittee's findings with Neurology Today.

WHY DID THE ACADEMY DECIDE TO REVIEW STUDIES ON MUSCLE CRAMP THERAPIES?

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AN AAN PANEL reviewed prospective studies on muscle cramps that have been published over the last 50 years.

Quinine sulfate is approved only for treating malaria, but it has been used for years off-label to treat muscle cramps. In 2006, the Food and Drug Administration (FDA) issued a formal warning against off-label use due to post-marketing surveillance reports of serious adverse events. The FDA has received 665 reports of adverse events, including 93 deaths, since 1969, but these records were not available to the review panel. There were no deaths reported in any of the studies we reviewed, but we calculated an adverse event rate of between 2 percent and 4 percent.

WHAT ARE THE POTENTIAL SIDE EFFECTS WITH QUININE AND ITS DERIVATIVES?

The most common serious side effects have primarily been hematologic complications, such as hemolytic uremic syndrome thrombotic

thrombocytopenia purpura, disseminated intravascular coagulation, and bleeding diathesis. The most consistently reported minor side effects have been headache, tinnitus, and bitter taste. There have also been reports of irregular heartbeats, deafness, and vision loss, but these have mostly been anecdotal.

Variable amounts of quinine derivatives are present in consumer products such as tonic water, and while there are a few case reports on their efficacy in muscle cramps, there are insufficient data to allow a specific comment on their use.

WHAT DID YOU FIND WITH REGARDING TO TREATMENT OPTIONS?

While muscle cramps are very common, there are few effective treatments. For a very long time, quinine and its derivates were the mainstay, and they have been used in many patients. We found that while they are likely effective, the benefits are modest, and the risks can be severe. In addition to bleeding issues, there is also risk of irregular heartbeats, hearing and vision loss, and hypersensitivity reactions. Quinine and its derivatives should therefore be avoided for routine use, but in patients without hematologic risk factors they can be considered for an individual therapeutic trial, once potential side effects are considered. They should be considered only when cramps are very disabling, no other agents relieve symptoms, and there is careful monitoring of side effects. Also, they should only be used after informing the patient of these serious side effects.

WHAT ABOUT OTHER MEDICATIONS?

A number of other medications and vitamins are fairly widely used, but evidence is sparse. Studies have looked at different antiepileptics, calcium channel blockers, and various vitamins, supplements, and minerals. We looked at these, but found little evidence that any of them work very well. Subjective evidence of their effectiveness has been reported, but they have not been studied in a vigorous manner, and making any recommendation is difficult.

Drugs like baclofen, carbamazepine, and oxcarbazepine are frequently used, but there are no published studies evaluating their efficacy for this indication. There have also been smaller studies suggesting that naftidrofuryl, vitamin B complex, lidocaine, and the calcium channel blocker diltiazem may be effective in some patients

One double-blind randomized controlled trial of 3600 mg per day of gabapentin, in 204 patients with amyotrophic lateral sclerosis and muscle cramps, found no difference between treatment and placebo scores. Another double-blind crossover trial of 30 mg of diltiazem hydrochloride on the number and intensity of cramps showed a statistically significant reduction (−5.84 to −0.16 cramps per two-week treatment phase, p = 0.04) in reducing the number of cramps over time in treated patients, but no effect on cramp intensity. It was also a small trial in 13 patients.

We concluded that vitamin B complex, naftidrofuryl, which is unavailable in this country, and calcium channel blockers like diltiazem, are possibly effective, and may be considered.

ARE THERE NONPHARMACOLOGICAL MEASURES, SUCH AS EXERCISE, THAT CAN EASE CRAMPS?

Many nonpharmacologic therapies are used by patients prior to prescriptiontreatment, but there is little evidence to support their use. Hydration, particularly for exercise-associated cramping, is frequently used by patients, but there are no formal studies supporting its use.

There is some evidence that stretching exercises can relieve cramps, especially at the outset, but it probably really does not help much, and you cannot stretch all the time. One study from 1979 suggested that stretching the affected muscles three times a day could reduce cramping, but another better designed study found no benefit on the frequency or number of cramps.

WHAT ABOUT VITAMINS AND MINERAL SUPPLEMENTS?

When the motor system is stressed, either by a neuromuscular disease or by a physiological stress such as dehydration or excessive exercise, cramps can occur or become more frequent. If caused by an electrolyte imbalance, it is important to identify and treat the underlying cause. Vitamins and supplements also might help, but the evidence is weak. One study of vitamin E (800 units) per day found no effect on the number or intensity of cramps, or sleeplessness due to cramps. Another small study in 28 patients found vitamin B complex (including 30 mg per day of vitamin B6) relieved cramps in 86 percent of treated patients who were not vitamin deficient, compared to placebo. However, completion and compliance rates were not detailed, so the value of the findings is not clear. Nonetheless, this should be studied more. Studies of magnesium sulfate (300 mg) and magnesium citrate (900 mg) have found no benefit.

WHAT ADDITIONAL RESEARCH IS NEEDED?

Given the lack of evidence of any convincing treatment, more research is needed on the potential efficacy and adverse effects of medications such as baclofen, carbamazepine, oxcarbazepine, levetiracetam, lidocaine, vitamin B complex, naftidrofuryl, gabapentin, magnesium, and calcium channel blockers. We were unable to find any good studies of gabapentin, carbamazepine, or oxcarbazepine. Future studies should also include an assessment of the impact of cramps on patients' quality of life, as well as other nonpharmacological interventions.

HOW DO YOU TREAT YOUR PATIENTS WITH MUSCLE CRAMPS?

I first recommend taking vitamin B complex and to try regular stretching exercises because these are safe, unless of course they take megadoses of vitamins, which can be dangerous. If their cramps are severe, I try them on anti-seizure medications like gabapentin or carbamazepine.

DISCLOSURE

Dr. So has received research funding from Pfizer, Inc., NeurogesX, Inc., and the NIH. He estimates that about 10 percent of his clinical effort is spent on EMG. He also holds equity in Sartoris, Inc. For a complete list of the authors and their disclosures, see the Feb. 23 assessment online at www.neurology.org.

References

Katzberg HD, Khan AH, So YT, Assessment: Symptomatic treatment for muscle cramps (an evidence-based review) - Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology 2010;74:691–696.