Muscle Cramps and Diuretic Therapy

Muscle cramps, notably nocturnal leg cramps, are common symptoms experienced by general medical patients, particularly the elderly. ¹ Their etiology is varied; most commonly, these cramps are idiopathic. With the notable (and relatively rare) exceptions of serious electrolyte imbalances including hypokalemia, hypomagnesemia and hypocalcemia, these cramps are typically benign in nature. Nevertheless, they can be bothersome. In addition to increased age, other risk factors for the development of muscle cramps include peripheral neurological disease and peripheral vascular disease, ² including venous insufficiency, ³ as well as arthritis, female gender, ⁴ and hemodialysis. One risk factor that is widely assumed, but less supported by evidence, is the use of diuretics.

Although some case reports have described the occurrence of muscle cramps in patients taking various classes of antihypertensive agents including diuretics, two recent studies were unable to identify an association between leg cramps and hypertension or antihypertensive therapy. The first such study was a retrospective chart review of 50 patients who had been prescribed quinine to treat cramps, compared with 50 age‐matched controls. ² It is difficult to exclude an association between diuretics and muscle cramps from this retrospective study because of its small size and the presence of a selection bias. Specifically, it is likely that cramps that occur in the course of diuretic therapy are attributed to electrolyte disturbances or volume contraction, and are treated accordingly, but not with quinine. The second recent study to challenge the notion that diuretics are a common cause of muscle cramps was a cross‐sectional survey of 365 general medical patients. ⁴ Although the prevalence of leg cramps in this cohort was 50%, no associations were found between these cramps and any medication except analgesics that were used to treat the cramps.

Nevertheless, a review of the Physicians' Desk Reference database (available at www.pdr.net) suggests a consistent association between diuretics and muscle cramps. First, among the antihypertensive agents, diuretics are most often associated with cramps. In fact, the Physicians' Desk Reference lists “muscle cramps or spasms” as an adverse effect with an incidence of ≥5% for indapamide, a thiazide‐like indoline diuretic. Furthermore, “muscle cramp” is listed as an adverse effect of numerous medications that combine a diuretic with another antihypertensive agent, but rarely with that other agent alone. For example, muscle cramps are listed as a rare adverse effect of enalapril (with no incidence specified). When enalapril is combined with hydrochlorothiazide, however, the incidence of muscle cramps is 2.7%.

The mechanism of diuretic‐associated cramping (if such an entity truly exists) is likely related to hypokalemia, hypomagnesemia, or volume contraction (with or without metabolic alkalosis). Hypocalcemia is a possible cause during therapy with loop‐diuretics such as furosemide, but is unlikely with the hypocalciuric thiazide‐type diuretics. Interestingly, potassium‐sparing diuretics, such as amiloride, are also associated with cramping. Thus volume contraction appears to be the one mechanism that is common to all classes of diuretics.

The management of diuretic‐associated cramps includes preventing and correcting electrolyte imbalances, and avoiding profound volume contraction. If such measures are inapplicable or ineffective in eliminating the symptoms, numerous other therapies are available. Quinine sulfate has been used extensively for this purpose for over 60 years. Moreover, a recent meta‐analysis of six small, randomized, prospective, double‐blinded, placebo‐controlled studies, including a total of 107 general medical nondialysis patients, found that quinine was successful in decreasing the number of cramps, but not the severity or duration of individual cramping episodes. ⁵ Nevertheless, quinine therapy is not without risk. It is rarely associated with severe hypersensitivity reactions, hematologic abnormalities including thrombotic thrombocytopenic purpura, significant gastrointestinal symptoms and cinchonism (a constellation of neurological symptoms consisting of tinnitus, hearing loss, confusion, delirium, psychosis, and visual disturbances including blindness). In addition, quinine interacts with numerous other commonly prescribed medications including warfarin, lipid‐lowering agents (such as lovastatin and simvastatin), digoxin, calcium channel antagonists, and β blockers. Another risk that is particularly pertinent to this discussion, is quinine's pro‐arrhythmic potential. Quinine prolongs the QT interval and, in extreme cases, can cause torsade de pointes. Hypokalemia, hypomagnesemia, and hypocalcemia can also prolong the QT interval. Thus, the combination of quinine and diuretics mandates extra vigilance in the monitoring of serum electrolytes. Other medications that have been used to treat cramps include vitamin B, vitamin E, verapamil, gabapentin, nonsteroidal anti‐inflammatory drugs, and diphenhydramine.

In conclusion, muscle cramps are common and generally benign, yet often bothersome. Their etiology is unclear, and an association with diuretic agents is possible. Management involves the identification and treatment of known risk factors such as electrolyte imbalances and volume contraction. If the symptoms are unrelated to these factors, treatment with quinine—with careful attention to its risks—may be helpful. Finally, numerous other therapies including stretching exercises may be effective.