Cinchonism

Leg cramps are a common problem, especially in the elderly. The differential diagnosis is extensive and includes the following conditions: true cramps, such as those related to heat, hemodialysis and electrolyte disturbances, as well as idiopathic cramps (the most common type); contractures occurring in conditions such as metabolic myopathies and thyroid disease; tetany, which is usually related to electrolyte disturbances, and dystonias, such as occupational cramps and those related to antipsychotic medications. Other leg problems that are not cramps, such as restless legs syndrome and periodic leg movements, also must be distinguished. The etiology of idiopathic leg cramps is not clear. Treatments for leg cramps include stretching exercises, quinine sulfate and vitamin E, but no treatment is conclusively effective. Nonetheless, in many patients relief of symptoms is achieved with one or more of these treatments.

Leg cramps are involuntary, painful contractions of muscles, usually in the calf but also in other areas of the leg. The diagnosis and management of this common problem can be frustrating for both physicians and patients.

Leg cramps affect both young and elderly persons, with variable rates of occurrence. In one recent survey,[1] 59 percent of outpatient veterans reported nocturnal leg cramps. Leg cramps are also common in pregnant women.

Cramps may not present with a set pattern, frequency or duration. They may occur intermittently during one day, or they may persist for several weeks. While leg cramps usually resolve spontaneously, some cases require treatment, based on the etiology of the cramping. Although several hypotheses have been proposed to explain the mechanism of idiopathic leg cramps, no definite cause has been established. This article reviews the pathogenesis, differential diagnosis and management of idiopathic leg cramps.

Pathogenesis of Leg Cramps

Layzer and Rowland[2] proposed that muscle cramps occur as a result of stimulation of the reflex arc and, possibly, through hyperexcitation of the motor neurons in any leg nerve or in the spinal cord. Weiner and Weiner[3] suggest that leg cramps occur when a maximally contracted muscle is stimulated, shortening the muscle beyond physiologic tolerance.

We recommend McGee's classification,[4] which is based on the presenting signs and symptoms of muscle cramps and includes true cramps, contractures, tetany and dystonia. True cramps, described as motor unit hyperactivity, include the ordinary cramp, cramps related to lower motor neuron disease, cramps due to heat, cramps in association with hemodialysis, cramps secondary to medications, and cramps due to fluid and electrolyte disturbances. Contractures are described as being electrically silent; these muscle cramps can be caused by metabolic myopathy, thyroid disease and McArdle's disease. The etiology of tetany, which is described as both sensory and motor unit hyperactivity, includes hypocalcemia, respiratory alkalosis, hypomagnesemia, hypokalemia and hyperkalemia. Simultaneous contraction of agonist and antagonist muscles is classified as dystonia, which includes occupational cramps (occurring in, for example, writers, musicians and miners) and cramps secondary to antipsychotic medications such as the phenothiazines.

Other medical conditions reportedly associated with muscle cramps include liver cirrhosis, sarcoidosis and lumbar spondylosis.[5-7] Medications reported to be associated with muscle cramping include the opioids (withdrawal), nicotinic acid, nifedipine (Adalat, Procardia) and clofibrate (Atromid-S).[8-10] Also, lead toxicity can cause cramping of the leg muscles.[10] A more complete listing of conditions associated with muscle cramps is given in Table 1.

Daniell[12] suggests that leg cramps may be prevented by stretching the calf muscles prophylactically in simple exercises.

QUININE SULFATE

For several decades, quinine sulfate has been widely used to treat leg cramps. However, early studies of its efficacy were poorly designed and included inadequate numbers of patients. In 1987, Warbuton and associates[11] conducted a double-blind, placebo-controlled crossover trial of quinine in 22 patients with leg cramps; this study failed to demonstrate a significant reduction in the frequency and severity of leg cramps with quinine bisulfate treatment, even with use of 300-mg doses. In 1986, Lim[13] reported that quinine therapy was ineffective in relieving leg cramps in a series of 25 patients. More recent trials, however, have found quinine to be superior to placebo in alleviating leg cramps.[14-17] Based on these later studies, quinine remains the recommended medication for the management of leg cramps.[17]

Quinine has long been used as an anti-malarial agent, but it also has analgesic and muscle relaxant properties. Although the method of action of quinine in leg cramps is not well understood, the drug is thought to decrease the excitability of the muscle end plate to nerve stimulation and to increase the muscle refractory period. Quinine is metabolized mainly by the liver, with peak blood levels occurring one to two hours after oral administration.[18] The half-life of quinine may be prolonged in elderly patients who are receiving long-term therapy.[18]

Adverse effects of quinine are rare but include cinchonism, which presents as nausea, vomiting, tinnitus and disturbed vision. This may progress to deafness, optic atrophy, severe gastrointestnal symptoms, renal failure, cardiac arrhythmias and death.[17] Visual toxicity can occur when quinine blood levels exceed 10 mg per L; sequelae range from visual blurring to permanent blindness.[19] Other side effects of quinine include hypoglycemia[20] and thrombocytopenia.[21] Quinine is contraindicated in pregnant women because of its abortifacient action and the possibility of fetal damage.[22]

We recommend a therapeutic trial of quinine in patients with leg cramps. The drug should be stopped if it produces no demonstrable benefit.

VITAMIN E

Vitamin E ([alpha]-tocopherol) is a compound present in wheat germ, rice and cottonseed oils. It is absorbed through the intestine and concentrated in the mitochondria, endoplasmic reticulum and plasma membranes. The idea of using vitamin E as a possible treatment for muscle cramps was first considered when relief of severe leg cramping was incidentally noted to occur in patients who were taking vitamin E.[23]

Based on results of a small, randomized, double-blind study, Roca and co-workers[24] suggested that vitamin E, 400 IU taken at night, is as effective as quinine in relieving leg cramps in dialysis patients. Ayers and Mihan[23] reported that vitamin E resulted in complete or nearly complete relief of leg cramps in 82 percent of their patients.[23] No adverse effects were noted. However, in a study comparing the efficacy and safety of quinine sulfate, vitamin E and placebo, Connolly and associates[25] noted that quinine, but not vitamin E, was superior to placebo in the treatment of leg cramps.

OTHER TREATMENTS

Various other drugs, such as verapamil (Calan, Isoptin), nifedipine and fluoride, have been used to treat leg cramps, but none has proved effective in well-designed studies. Because the placebo effect can be very marked in this condition, reports of efficacy and anecdotal accounts should be viewed with caution.

Final Comment

The treatment of leg cramps can be difficult. The first step is to exclude all potential iatrogenic or treatable causes. For the patient with mild cramps, a trial of stretching exercises for the affected muscles may be useful; these exercises should be performed before sleep and during the cramps. For cases in which exercises are ineffective, we suggest a trial of quinine sulfate, initiated at 200 mg per day and increased to 300 mg per day over five to eight days. An eight-day trial is usually adequate to determine whether quinine is effective in a particular patient. All patients should be properly counseled and monitored for side effects. At this time, the literature does not support the use of drugs other than quinine in the treatment of leg cramps.

The authors thank Professor Eugene Furth of the Department of Medicine at East Carolina University, Greenville, N.C., for his helpful suggestions during the preparation of this manuscript. The authors also thank Anuradha Rabindranath-Antony for assisting in the preparation of the original manuscript.

REFERENCES

[1.] Oboler SK, Prochazka AV, Meyer TJ. Leg symptoms in outpatient veterans. West J Med 1991;155:256-9. [2.] Layzer RB, Rowland LP. Cramps. N Engl J Med 1971;285:31-40. [3.] Weiner IH, Weiner HL. Nocturnal leg muscle cramps. JAMA 1980;244:2332-3. [4.] McGee SR. Muscle cramps. Arch Intern Med 1990; 150:511-8. [5.] Konikoff F, Theodor E. Painful muscle cramps. A symptom of liver cirrhosis? J Clin Gastroenterol 1986;8:669-72. [6.] Janssen M, Dijkmans BA, Eulderink F. Muscle cramps in the calf as presenting symptom of sarcoidosis. Ann Rheum Dis 1991;50:51-2. [7.] Sugar O. Causes of night cramps [Letter]. JAMA 1985;253:775-6. [8.] Litin SC, Anderson CF. Nicotinic acid-associated myopathy: a report of three cases. Am J Med 1989; 86:481-3. [9.] Keidar S, Binenboim C, Palant A. Muscle cramps during treatment with nifedipine. Br Med J [Clin Res] 1982;285:1241-2. [10.] Cutler P. Queries and minor notes: then and now. JAMA 1984;252:98. [11.] Warburton A, Royston JP, O'Neill CJ, Nicholson PW, Jee RD, Denham MJ, et al. Br J Clin Pharmacol 1987;23:459-65. [12.] Daniell HW. Simple cure for nocturnal leg cramps [Letter]. N Engl J Med 1979;301:216. [13.] Lim SH. Randomized double-blind trial of quinine sulphate for nocturnal leg cramp. Br J Clin Pract 1986;40:462. [14.] Kaji DM, Ackad A, Nottage WG, Stein RM. Prevention of muscle cramps in haemodialysis patients by quinine sulphate. Lancet 1976;2(7976):66-7. [15.] Jones K, Castleden CM. A double-blind comparison of quinine sulphate and placebo in muscle cramps. Age Ageing 1983;12:155-8. [16.] Fung MC, Holbrook JH. Placebo-controlled trial of quinine therapy for noctunal leg cramps. West J Med 1989;151:42-4. [17.] Quinine for "night cramps." Med Lett Drugs Ther 1986;28:110. [18.] Berlin CM, Stackman JM, Vesell ES. Quinine-induced alterations in drug disposition. Clin Pharmacol Ther 1975;18:670-9. [19.] Smilkstein MJ, Kulig KW, Rumack BH. Acute toxic blindness: unrecognized quinine poisoning. Ann Emerg Med 1987;16:98-101. [20.] Harats N, Ackerman Z, Shalit M. Quinine-related hypoglycemia [Letter]. N Engl J Med 1984;310:1331-2. [21.] Siroty RR. Purpura on the rocks--with a twist. JAMA 1976;235:2521-2. [22.] Sidorov J. Quinine sulfate for leg cramps: does it work? J Am Geriatr Soc 1993;41:498-500. [23.] Ayres S Jr, Mihan R. Leg cramps (systremma) and "restless legs" syndrome. Response to vitamin E (tocopherol). Calif Med 1969;111:87-91. [24.] Roca AO, Jarjoura D, Blend D, Cugino A, Rutecki GW, Nuchikat PS, et al. Dialysis leg cramps. Efficacy of quinine verses vitamin E. ASAIO J 1992;38:481-5. [25.] Connolly PS, Shirley EA, Wasson JH, Nierenberg DW. Treatment of nocturnal leg cramps. A crossover trial of quinine vs vitamin E. Arch Intern Med 1992;152:1877-80.

The Authors

JOHN D. RILEY, M.D. is currently a general medicine fellow at Indiana University School of Medicine, Indianapolis. Dr. Riley received his medical degree from the University of South Florida College of Medicine, Tampa, and he completed a residency in internal medicine at East Carolina University School of Medicine, Greenville, N.C.

SURESH J. ANTONY, M.D., F.R.C.P. is currently serving a fellowship in infectious diseases at Vanderbilt University School of Medicine, Nashville, Tenn. A graduate of the University of Mysore, India, Dr. Antony completed an internal medicine residency at East Carolina University School of Medicine.

Address correspondence to Suresh J. Antony, M.D., Vanderbilt University School of Medicine, Division of Infectious Diseases, A-3310 Medical Center North, Nashville, 7N 37232.

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