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Clinical Epidemiology of Nocturnal Leg Cramps in Male Veterans
Clinical Epidemiology of Nocturnal Leg Cramps in Male Veterans SALLY G. HASKELL, MD,*t
NICHOLAS H. FIEBACH, MD*
ABSTRACT: This article describes patients with nocturnal leg cramps concerning their age, medical problems, and medications, and reviews any medical evaluation performed for the complaint of nocturnal leg cramps. Provided is a retrospective chart review of 50 patients who took quinine sulfate for nocturnal leg cramps. These patients were identified through computerized pharmacy records. A control group was chosen from age-matched patients who took medications other than quinine during the study period. In a universityaffiliated Veterans Administration hospital, patients with nocturnal leg cramps had a significantly higher median number of medical problems than controls. Cardiovascular diseases and neurological diseases were significantly more common in patients with nocturnal leg cramps (cases) than in those without (controls) (82% versus 64% and 36% versus 18%, respectively). The most striking differences between patients with cramps and controls were peripheral vascular disease (34% versus 12%, P = 0.09) and peripheral neurological deficit (12% versus 0%, P =0.012). Patients with nocturnal leg cramps were prescribed significantly more medications than were controls, but no specific medication or type of medication was prescribed more frequently to patients with cramps (other than quinine). Results suggested that men with nocturnal leg cramps have greater medical comorbidity and are prescribed more medications than agematched control patients. Unlike in previous studies, no evidence was found that specific medications, such as diuretics, betaagonists, or calcium-channel antagonists are associated with nighttime cramps. The significantly inFrom the *Section of General Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, and the tVeterans Administration Medical Center, West Haven, Connecticut. Submitted April 16, 1996; accepted November 14, 1996. Correspondence: Sally Haskell, MD, Department of Medicine, VA Medical Center, 950 Campbell Avenue, West Haven, CT 06516.
210
creased frequency of peripheral vascular disease and peripheral neurologic deficits in patients with nocturnal leg cramps raised the possibility that these problems contribute to the occurrence of cramps. Although the size of the study and its methodologic limitations preclude definitive conclusions, areas for research to clarify the clinical· epidemiology of nocturnal leg cramps are suggested. KEY INDEXING TERMS: Cramps; Muscle cramps; Leg; Quinine. [Am J Med Sci 1997;313(4):210-214.]
M
any patients in general medical practice complain of nocturnal leg cramps. However, epidemiologic data describing patient populations with leg cramps are limited and little is known about factors that predispose certain patients to nocturnal leg cramps. Leg cramps are common in the elderly1 and in other groups of patients, such as those with cancer2 or those undergoing hemodialysis. 3 Leg cramps have occurred in patients taking specific medications, including diuretics,4 betaagonists,5 and nifedipine. 6 Although most nocturnal leg cramps are considered idiopathic, specific contributing causes of muscle cramps have been cited, including nerve root compression or peripheral nerve injury,7,8 peripheral vascular disease, 9 hypovolemia and hyponatremia, 10 hypoglycemia,l1 and thyroid disease. 12 Hypokalemia, hypomagnesemia, and hypocalcemia often are mentioned in association with leg cramps but are probably a cause of tetany more commonly than true cramps.13 Although the pathophysiology of the muscle cramp remains controversial, neurophysiologic studies indicate that muscle cramps originate in peripheral motor neuron terminals and may be caused by multiple factors that generate electrical irritability of the motor nerve terminal. 14 Nocturnal leg cramps are thought to be a benign but bothersome symptom and often are treated symptomatically with quinine sulfate. A recent metaanalysis, which pooled data from six clinical trials, indicated that quinine reduces the frequency of nocturnal leg cramps.15 Nevertheless, the Food April 1997 Volume 313 Number 4
Haskell and Fiebach
and Drug Administration removed quinine from the over-the-counter market because of doubts about its effectiveness and concern about potential toxicity and life-threatening hypersensitivity reactions. 16 We undertook a retrospective study of patients with nocturnal leg cramps (case patients) and agedmatched controls in a university-affiliated Veterans Administration hospital. We sought to describe patients with night cramps regarding their age, medical problems, and medications. We were interested in any diagnostic evaluation that was performed after the initial complaint of nocturnal leg cramps was noted and in the frequency of any specific abnormalities that were discovered in the physical examination and laboratory evaluation. Methods
The computerized pharmacy system at the West Haven Veterans Mfairs Medical Center was used to obtain the names and hospital numbers of all patients who were prescribed quinine sulfate during a 6 month period (October 1, 1991 through April 1, 1992). Because there was no other current indication for the use of quinine sulfate it was presumed that all of these patients had complained of nocturnal leg cramps. The ambulatory clinic and hospital records of these patients were reviewed by one of the authors. Patients were included in the study if the treating physician indicated an assessment of nocturnalleg cramps. Patients were not included unless the actual words "leg cramps" were in the record. Patients with less specific descriptions of leg pain were excluded, as were patients whose records showed no mention ofleg cramps. The charts ofthese excluded patients were reviewed, and there were no apparent clinical or demographic differences between them and the patients who were included. A control group was formed by obtaining a list of patients who received any prescription other than quinine sulfate from the West Haven Veterans Affairs Medical Center pharmacy during the same study period. For each patient with cramps, an agematched control patient was chosen by taking the first patient, in alphabetical order, on this list who had the same year of birth as the case patient. The medical records of these patients also were reviewed by one of the authors, and any potential control patient whose chart showed nocturnal leg cramps during the study period was excluded. If the medical record for a potential control patient could not be found, the next patient on the alphabetical pharmacy list with the same year of birth was selected. The ambulatory clinic and hospital records of patients with leg cramps and control patients were reviewed to determine the patient's age, problem, and medication lists. Patient medical problems, listed on the problem list and verified in the clinic notes, were recorded. Specific medical problems were recorded THE AMERICAN JOURNAL Of THE MEDICAL SCIENCES
as noted in the medical record and grouped into more inclusive categories. General disease categories included the following: musculoskeletal, endocrine, psychiatric, substance abuse, cardiovascular, dermatologic, surgical, oncologic, pulmonary, neurologic, gastrointestinal, thromboembolic, ophthalmologic, infectious, genitourinary, renal, otolaryngologic diseases, and miscellaneous diagnoses. For example, the entry "CVA with right hemiparesis" was counted as stroke, any neurologic deficit, and any neurologic disease. Medication lists were recorded from the clinic notes. Medications also were grouped into categories, including diuretics, beta agonists, nonsteroidal antiinflammatory agents, narcotics, benzodiazepines, antihistamines, calcium-channel antagonists, betaantagonists, nitrates, lipid-lowering agents, oral hypoglycemics, histamine-2 receptor antagonists, angiotensin converting enzyme inhibitors, and other miscellaneous drugs. For case patients any specific evaluation ofnocturnalleg cramps was recorded whether vascular, neurologic, or musculoskeletal examinations were performed, whether any laboratory evaluation was directed specifically toward the workup of leg cramps, whether there was further evaluation or referral, and whether the nocturnal leg cramps were attributed to a specific predisposing factor by the patient's physician. Patients with nocturnal leg cramps were compared to controls with respect to the number and types of their medical problems and medications. The statistical significance ofthese comparisons was assessed using chi-square test for categoric variables and the Wilcoxon rank sum test for continuous variabIes. 17 Results
Pharmacy records showed that 116 patients had been prescribed quinine sulfate during the study period. Ofthe initial 116 case patients charts, 74 (64%) were available for review at the time of the study. A similar percentage of charts from case patients and controls were available. Medical record retrieval was limited by the availability of charts through the medical record system. Of the 74 available charts 52 showed the complaint of nocturnal leg cramps. The 52 patients with nocturnal leg cramps included 50 men and 2 women. Because the two women could not be matched with controls for age and sex, they were excluded; the final study group consisted of all men, 50 with leg cramps and 50 age-matched controls. Median age was 70 years and ranged from ages 46 to 80. More than 120 specific medical diagnoses were recorded for all subjects. Patients with nocturnal leg cramps had a median of 5 problems, whereas patients in the control group had a median of3.5 medi211
Nocturnal Leg Cramps
Table 1. Frequency of Medical Problems in Patients with Nocturnal Leg Cramps and in Age-Matched Control Patients
Medical Problems
Cases (%) (n = 50)
Controls (%) (n = 50)
P Value
Cardiovascular disease Coronary disease Peripheral vascular disease Neurologic Disease Any neurologic deficit Peripheral neurologic deficit Gastritis
41 (82) 31 (62) 17 (34) 18 (36) 14 (28) 6 (12) 4 (8)
32 (64) 20 (40) 6 (12) 9 (18) 5 (10) 0(0) 0(0)
.043 .028 .009 .043 .022 .012 .041
cal problems (P = 0.0007). Cardiovascular disease and neurologic diseases both were significantly more frequent in the case group than in the control group (82% versus 64% and 36% versus 18%, respectively [Table 1]). When these broad categories of diseases were broken down into specific medical problems, we found that coronary artery disease was present in 62% of the case patients and in 40% of the controls (P = 0.028), and peripheral vascular disease was present in 34% of the case patients and in 12% ofthe controls (P = 0.009). Similarly, when the category of neurologic diseases was broken down into any neurologic deficit and peripheral neurologic deficit (compression neuropathy, radiculopathy or peripheral neuropathy), we found that any neurologic deficit was present in 28% of the case patients and in 10% of the controls (P = 0.022), whereas a peripheral neurologic deficit was present in 12% of the case patients and in 0% of the controls (P = 0.012). No significant differences between case patients and controls in the occurrence of other disease categories or specific medical problems was found, although gastritis occurred more frequently in case patients (8% versus 0%, P = 0.041). Approximately 100 specific medications were recorded for all subjects. Patients with nocturnal leg cramps were prescribed more medications overall than patients in the control group; the median number of medications was 4 and 3, respectively (P = 0.015). No specific medication was prescribed more frequently to case patients than to controls. When the medications were grouped into categories, such as diuretics, calcium' channel blockers, and others, we found that nitrates and antidepressants were prescribed significantly more frequently to case patients than to controls. A nitrate preparation (P = 0.032) was prescribed to 32% of the case patients and to 14% of the controls, and 14% of the case patients and 2% of the controls were prescribed an antidepressant (P = 0.027). No other classes of medication, including diuretics (with or without potassium supplements or potassium-sparing agents), betaagonists, and calcium-channel blockers, were more frequently prescribed to case patients than to controls. Laboratory evaluations were performed specifi212
cally for the evaluation of leg cramps in a minority of cases, including electrolytes in 35% of patients, calcium in 17%, and magnesium in 7%. None ofthese tests were recorded as abnormal. No patient underwent thyroid function tests to evaluate leg cramps. In response to the complaint of nocturnal cramps, vascular examination was noted in 40% ofthe charts of case patients, a neurologic examination in 19%, and a musculoskeletal examination in 15%. The patients' physicians attributed their cramps to a specific predisposing factor in only 27%, including peripheral neuropathy, stroke, radiculopathy, leg injury, and the proximal effects of distal amputation. Cramps were thought caused by dialysis and diuretics in one patient each, although no electrolyte abnormalities were noted. Discussion
This small retrospective study was intended to be a preliminary exploration of the clinical epidemiology of nocturnal leg cramps. Limitations of the study include indirect identification of cases and controls through pharmacy records, retrospective reliance on the medical record to ascertain diagnostic and therapeutic information, and the inability to include case patients whose medical records were not available or whose records did not document the complaint of nocturnal leg cramps, although they had been prescribed quinine. This study was based on the treating physicians' diagnoses of nocturnal leg cramps, and misclassification by them of other types of leg pain may have occurred. This study does not provide definitive information concerning the etiologies of nocturnal leg cramps. Nevertheless, we believe this limited cohort is representative of many ambulatory veteran and other male hospital clinic patients with bothersome nocturnalleg cramps, and the results provide interesting preliminary descriptive information that may be useful in directing future studies. Results indicate that among veterans prescribed quinine sulfate, nocturnal leg cramps occur most commonly in patients older than 50. This group of patients with nocturnal leg cramps was compared with an age-matched population without nocturnal April 1997 Volume 313 Number 4
Haskell and Fiebach
leg cramps. Significantly greater numbers of medical problems were found, and they were prescribed significantly more medications than the control group. A higher incidence of neurologic and cardiovascular disease (most significantly, peripheral neurologic and peripheral vascular disease) was found in patients with nocturnal leg cramps than in the agematched controls. Although muscle cramping can occur in lower motor neuron diseases,18,19 only anecdotal reports 7,8 were found that suggested leg cramps are common in patients with nerve root compression syndromes. In this patient sample, peripheral neuropathy and radiculopathy was found to be more common in patients with nocturnal leg cramps than in the agematched control group. This suggests that peripheral neurologic injury may be associated with nocturnal leg cramps in some patients. It was reported previously that peripheral vascular disease was not a cause of nocturnal leg cramps.20 However, a general survey of rest cramps21 in a British population in 1994 found a significant association between impaired lower extremity circulation and nocturnal cramps. The higher incidence of cardiovascular disease and peripheral vascular disease in patients with nocturnal leg cramps compared with controls in this study raises the possibility that vascular disease predisposes patients to the development of nocturnal leg cramps. This association may occur because of lower extremity ischemia, disuse, atrophy, or other trophic changes; however, these possibilities remain speculative. Possibly, symptoms of claudication and rest pain are misdiagnosed as nocturnal leg cramps, increasing the apparent incidence of peripheral vascular disease in a study group of patients with cramps. Although nocturnal leg cramps are common in cancer, cirrhosis, and hemodialysis patients, these diagnoses were not common in the sample we studied. The greater degree of medical comorbidity in patients with leg cramps compared with controls in this study suggests an association with generalized debility, possibly reflecting inactivity, weakness, or poor nutritional intake as potential etiologic factors. Case patients in this study were prescribed a greater number of medications than controls. This may reflect the greater degree of medical comorbidity in patients with leg cramps, although, patients with cramps might be more "reactive" or more likely to complain of somatic symptoms than controls and therefore more likely to be prescribed more medications. Nocturnal leg cramps have been associated with the use of diuretics,4 calcium channel antagonists,5 and betaagonists. 6 Unlike previous studies, none of these medications was used more commonly in these case patients than in the control group. Because of the small size ofthe study, the possibility of an as soTHE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
ciation between these or other medications and nocturnal leg cramps cannot be excluded completely. Nitrates and tricyclic antidepressants were prescribed more to patients with nocturnal leg cramps than to controls. No other reports of any association of these medications with nocturnal leg cramps are known. We attribute the association of nocturnal leg cramps and nitrates to the confounding effects ofthe vascular disease for which they were prescribed. The significance of the association of nighttime cramps with antidepressants is not olear, especially because most were tricyclic, and tricycliclike medications, such as methocarbamol, are used as muscle relaxants. No association between leg cramps and any psychiatric diagnosis, including depression, was found. It may be that depressed patients receiving drug therapy are more likely to report and to be treated for somatic symptoms, such as cramps. A diagnostic evaluation, including physical examination or laboratory testing, was recorded in a minority of the charts of patients with nocturnal leg cramps. A possible predisposing factor for nocturnal leg cramps was identified by the patients' physicians in only 27% of the patients. This contrasts with higher estimates of specific causative factors previously reported in selected groups of patients (eg, 89% in a group of cancer patients2). Although the number of cases and controls in this study was relatively small, numerous comparisons were made between the two groups and many diseases and medications were considered. This increased the chance of a type I error in any association that was found. Although the results of all comparisons are presented with P < 0.05, those associations that are biologically plausible or consistent with previous studies and that have smaller P values (eg, the association between nocturnal leg cramps and peripheral neurologic deficit and peripheral vascular disease) are emphasized. We are inclined to regard less plausible associations with borderline P values, such as the more frequent occurrence of gastritis in patients with nighttime cramps, as a result of chance. We point out that the selection of patients based on their prescription of quinine sulfate excluded those with nocturnal leg cramps who were not treated with this therapy, possibly excluding those with less severe or persistent symptoms and those with potential contraindications to quinine (such as preexisting abnormalities ofliver function, thrombocytopenia, or cardiac disease). Some patients were excluded who were prescribed quinine but who did not have nocturnal leg cramps noted in the chart. Although the charts of these patients suggested they did not differ clinically or demographically, it is possible that these patients had less severe or less persistent symptoms. The results indicate that nocturnal leg cramps oc213
Nocturnal Leg Cramps
cur most commonly among older patients with comorbid illnesses and suggest areas for further research. Larger, controlled studies of patients with nocturnal leg cramps could assess the prevalence of peripheral neurologic and vascular abnormalities, examine the relations between cramps and functional status and disability, and reexamine more definitively the apparent lack of association of specific medications with the occurrence of nocturnal leg cramps. References 1. Baltadano, N, Gallo BV, Weidler DJ. Verapamil vs. quinine in recumbent nocturnal leg cramps in the elderly. Arch Intern Med. 1988; 148:1969-70. 2. Steiner I, Seigal T. Muscle cramps in cancer patients. Cancer. 1988;63:574-7. 3. Kaji DM, Ackad A, Nottage WG, Stein RM. Prevention of muscle cramps in hemodialysis patients by quinine sulfate. Lancet. 1976;2:66-7. 4. Physician's Desk Reference, 47th Edition. New Jersey: Medical Economics Data Production Company, 1993. 5. Zelman S. Terbutaline and muscular symptoms. JAMA. 1978; 239:930. 6. Keidar S, Binenboim C, Palant A. Muscle cramps during treatment with nifedipine. Br Med J. 1982;285:1241-2. 7. Sugar O. Causes of night cramps. JAMA. 1985;235:775-6.
214
8. Rish BL. Nerve root compression and night cramps. JAMA. 1985; 254:361. 9. Young JB, Javid M, George J. Rest cramps in the elderly. Journal of the Royal College of Physicians of London. 1989;20:103-6. 10. Knochel JP. Neuromuscular manifestation of electrolyte disorders. Am J Med. 1982;72:521-5. 11. Robert HJ. Spontaneous leg cramps and "restless legs" due to diabetogenic hyperinsulinism: Observations on 131 patients. J Am Geriatr Soc. 1965; 13:602-38. 12. Araki S, Terao A, Matsumoto I, Narazaki T, Kuroiwa Y. Muscle cramps in chronic thyrotoxic myopathy. Arch Neurol. 1986; 19:315-20. 13. McGee SR. Muscle cramps. Arch Intern Med. 1990; 150:5118. 14. Lazer RB. The origin of muscle fasciculation and cramps. Muscle and Nerve. 1994; 17:1243-9. 15. Man-Son-Hing M, Wells G. Meta-analysis of the efficacy of quinine for treatment of nocturnal leg cramps in elderly people. BMJ. 1995;310:13-7. 16. Nightingale S. Quinine for nocturnal leg cramps. ACP J Club. 1995; 123(3):86-87. 17. SAS/STAT User's Guide, Release 6.03 Edition. Cary, NC: SAS Institute Inc,; 1988. 18. Mulder DW. The clinical symptoms of amyotrophic lateral sclerosis. Mayo Clin Proc. 1957;32:427. 19. Hudson AJ, Brown WF, Gilbert JJ. The muscular pain fasciculation syndrome. Neurology. 1973; 28:1105-9. 20. Cutler P. Cramps in the legs and feet. JAMA. 1984;252:98. 21. Naylor JR, Young JB. A general population survey of rest cramps. Age and Aging. 1994;23:418-20.
April 1997 Volume 313 Number 4
NICHOLAS H. FIEBACH, MD*
ABSTRACT: This article describes patients with nocturnal leg cramps concerning their age, medical problems, and medications, and reviews any medical evaluation performed for the complaint of nocturnal leg cramps. Provided is a retrospective chart review of 50 patients who took quinine sulfate for nocturnal leg cramps. These patients were identified through computerized pharmacy records. A control group was chosen from age-matched patients who took medications other than quinine during the study period. In a universityaffiliated Veterans Administration hospital, patients with nocturnal leg cramps had a significantly higher median number of medical problems than controls. Cardiovascular diseases and neurological diseases were significantly more common in patients with nocturnal leg cramps (cases) than in those without (controls) (82% versus 64% and 36% versus 18%, respectively). The most striking differences between patients with cramps and controls were peripheral vascular disease (34% versus 12%, P = 0.09) and peripheral neurological deficit (12% versus 0%, P =0.012). Patients with nocturnal leg cramps were prescribed significantly more medications than were controls, but no specific medication or type of medication was prescribed more frequently to patients with cramps (other than quinine). Results suggested that men with nocturnal leg cramps have greater medical comorbidity and are prescribed more medications than agematched control patients. Unlike in previous studies, no evidence was found that specific medications, such as diuretics, betaagonists, or calcium-channel antagonists are associated with nighttime cramps. The significantly inFrom the *Section of General Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, and the tVeterans Administration Medical Center, West Haven, Connecticut. Submitted April 16, 1996; accepted November 14, 1996. Correspondence: Sally Haskell, MD, Department of Medicine, VA Medical Center, 950 Campbell Avenue, West Haven, CT 06516.
210
creased frequency of peripheral vascular disease and peripheral neurologic deficits in patients with nocturnal leg cramps raised the possibility that these problems contribute to the occurrence of cramps. Although the size of the study and its methodologic limitations preclude definitive conclusions, areas for research to clarify the clinical· epidemiology of nocturnal leg cramps are suggested. KEY INDEXING TERMS: Cramps; Muscle cramps; Leg; Quinine. [Am J Med Sci 1997;313(4):210-214.]
M
any patients in general medical practice complain of nocturnal leg cramps. However, epidemiologic data describing patient populations with leg cramps are limited and little is known about factors that predispose certain patients to nocturnal leg cramps. Leg cramps are common in the elderly1 and in other groups of patients, such as those with cancer2 or those undergoing hemodialysis. 3 Leg cramps have occurred in patients taking specific medications, including diuretics,4 betaagonists,5 and nifedipine. 6 Although most nocturnal leg cramps are considered idiopathic, specific contributing causes of muscle cramps have been cited, including nerve root compression or peripheral nerve injury,7,8 peripheral vascular disease, 9 hypovolemia and hyponatremia, 10 hypoglycemia,l1 and thyroid disease. 12 Hypokalemia, hypomagnesemia, and hypocalcemia often are mentioned in association with leg cramps but are probably a cause of tetany more commonly than true cramps.13 Although the pathophysiology of the muscle cramp remains controversial, neurophysiologic studies indicate that muscle cramps originate in peripheral motor neuron terminals and may be caused by multiple factors that generate electrical irritability of the motor nerve terminal. 14 Nocturnal leg cramps are thought to be a benign but bothersome symptom and often are treated symptomatically with quinine sulfate. A recent metaanalysis, which pooled data from six clinical trials, indicated that quinine reduces the frequency of nocturnal leg cramps.15 Nevertheless, the Food April 1997 Volume 313 Number 4
Haskell and Fiebach
and Drug Administration removed quinine from the over-the-counter market because of doubts about its effectiveness and concern about potential toxicity and life-threatening hypersensitivity reactions. 16 We undertook a retrospective study of patients with nocturnal leg cramps (case patients) and agedmatched controls in a university-affiliated Veterans Administration hospital. We sought to describe patients with night cramps regarding their age, medical problems, and medications. We were interested in any diagnostic evaluation that was performed after the initial complaint of nocturnal leg cramps was noted and in the frequency of any specific abnormalities that were discovered in the physical examination and laboratory evaluation. Methods
The computerized pharmacy system at the West Haven Veterans Mfairs Medical Center was used to obtain the names and hospital numbers of all patients who were prescribed quinine sulfate during a 6 month period (October 1, 1991 through April 1, 1992). Because there was no other current indication for the use of quinine sulfate it was presumed that all of these patients had complained of nocturnal leg cramps. The ambulatory clinic and hospital records of these patients were reviewed by one of the authors. Patients were included in the study if the treating physician indicated an assessment of nocturnalleg cramps. Patients were not included unless the actual words "leg cramps" were in the record. Patients with less specific descriptions of leg pain were excluded, as were patients whose records showed no mention ofleg cramps. The charts ofthese excluded patients were reviewed, and there were no apparent clinical or demographic differences between them and the patients who were included. A control group was formed by obtaining a list of patients who received any prescription other than quinine sulfate from the West Haven Veterans Affairs Medical Center pharmacy during the same study period. For each patient with cramps, an agematched control patient was chosen by taking the first patient, in alphabetical order, on this list who had the same year of birth as the case patient. The medical records of these patients also were reviewed by one of the authors, and any potential control patient whose chart showed nocturnal leg cramps during the study period was excluded. If the medical record for a potential control patient could not be found, the next patient on the alphabetical pharmacy list with the same year of birth was selected. The ambulatory clinic and hospital records of patients with leg cramps and control patients were reviewed to determine the patient's age, problem, and medication lists. Patient medical problems, listed on the problem list and verified in the clinic notes, were recorded. Specific medical problems were recorded THE AMERICAN JOURNAL Of THE MEDICAL SCIENCES
as noted in the medical record and grouped into more inclusive categories. General disease categories included the following: musculoskeletal, endocrine, psychiatric, substance abuse, cardiovascular, dermatologic, surgical, oncologic, pulmonary, neurologic, gastrointestinal, thromboembolic, ophthalmologic, infectious, genitourinary, renal, otolaryngologic diseases, and miscellaneous diagnoses. For example, the entry "CVA with right hemiparesis" was counted as stroke, any neurologic deficit, and any neurologic disease. Medication lists were recorded from the clinic notes. Medications also were grouped into categories, including diuretics, beta agonists, nonsteroidal antiinflammatory agents, narcotics, benzodiazepines, antihistamines, calcium-channel antagonists, betaantagonists, nitrates, lipid-lowering agents, oral hypoglycemics, histamine-2 receptor antagonists, angiotensin converting enzyme inhibitors, and other miscellaneous drugs. For case patients any specific evaluation ofnocturnalleg cramps was recorded whether vascular, neurologic, or musculoskeletal examinations were performed, whether any laboratory evaluation was directed specifically toward the workup of leg cramps, whether there was further evaluation or referral, and whether the nocturnal leg cramps were attributed to a specific predisposing factor by the patient's physician. Patients with nocturnal leg cramps were compared to controls with respect to the number and types of their medical problems and medications. The statistical significance ofthese comparisons was assessed using chi-square test for categoric variables and the Wilcoxon rank sum test for continuous variabIes. 17 Results
Pharmacy records showed that 116 patients had been prescribed quinine sulfate during the study period. Ofthe initial 116 case patients charts, 74 (64%) were available for review at the time of the study. A similar percentage of charts from case patients and controls were available. Medical record retrieval was limited by the availability of charts through the medical record system. Of the 74 available charts 52 showed the complaint of nocturnal leg cramps. The 52 patients with nocturnal leg cramps included 50 men and 2 women. Because the two women could not be matched with controls for age and sex, they were excluded; the final study group consisted of all men, 50 with leg cramps and 50 age-matched controls. Median age was 70 years and ranged from ages 46 to 80. More than 120 specific medical diagnoses were recorded for all subjects. Patients with nocturnal leg cramps had a median of 5 problems, whereas patients in the control group had a median of3.5 medi211
Nocturnal Leg Cramps
Table 1. Frequency of Medical Problems in Patients with Nocturnal Leg Cramps and in Age-Matched Control Patients
Medical Problems
Cases (%) (n = 50)
Controls (%) (n = 50)
P Value
Cardiovascular disease Coronary disease Peripheral vascular disease Neurologic Disease Any neurologic deficit Peripheral neurologic deficit Gastritis
41 (82) 31 (62) 17 (34) 18 (36) 14 (28) 6 (12) 4 (8)
32 (64) 20 (40) 6 (12) 9 (18) 5 (10) 0(0) 0(0)
.043 .028 .009 .043 .022 .012 .041
cal problems (P = 0.0007). Cardiovascular disease and neurologic diseases both were significantly more frequent in the case group than in the control group (82% versus 64% and 36% versus 18%, respectively [Table 1]). When these broad categories of diseases were broken down into specific medical problems, we found that coronary artery disease was present in 62% of the case patients and in 40% of the controls (P = 0.028), and peripheral vascular disease was present in 34% of the case patients and in 12% ofthe controls (P = 0.009). Similarly, when the category of neurologic diseases was broken down into any neurologic deficit and peripheral neurologic deficit (compression neuropathy, radiculopathy or peripheral neuropathy), we found that any neurologic deficit was present in 28% of the case patients and in 10% of the controls (P = 0.022), whereas a peripheral neurologic deficit was present in 12% of the case patients and in 0% of the controls (P = 0.012). No significant differences between case patients and controls in the occurrence of other disease categories or specific medical problems was found, although gastritis occurred more frequently in case patients (8% versus 0%, P = 0.041). Approximately 100 specific medications were recorded for all subjects. Patients with nocturnal leg cramps were prescribed more medications overall than patients in the control group; the median number of medications was 4 and 3, respectively (P = 0.015). No specific medication was prescribed more frequently to case patients than to controls. When the medications were grouped into categories, such as diuretics, calcium' channel blockers, and others, we found that nitrates and antidepressants were prescribed significantly more frequently to case patients than to controls. A nitrate preparation (P = 0.032) was prescribed to 32% of the case patients and to 14% of the controls, and 14% of the case patients and 2% of the controls were prescribed an antidepressant (P = 0.027). No other classes of medication, including diuretics (with or without potassium supplements or potassium-sparing agents), betaagonists, and calcium-channel blockers, were more frequently prescribed to case patients than to controls. Laboratory evaluations were performed specifi212
cally for the evaluation of leg cramps in a minority of cases, including electrolytes in 35% of patients, calcium in 17%, and magnesium in 7%. None ofthese tests were recorded as abnormal. No patient underwent thyroid function tests to evaluate leg cramps. In response to the complaint of nocturnal cramps, vascular examination was noted in 40% ofthe charts of case patients, a neurologic examination in 19%, and a musculoskeletal examination in 15%. The patients' physicians attributed their cramps to a specific predisposing factor in only 27%, including peripheral neuropathy, stroke, radiculopathy, leg injury, and the proximal effects of distal amputation. Cramps were thought caused by dialysis and diuretics in one patient each, although no electrolyte abnormalities were noted. Discussion
This small retrospective study was intended to be a preliminary exploration of the clinical epidemiology of nocturnal leg cramps. Limitations of the study include indirect identification of cases and controls through pharmacy records, retrospective reliance on the medical record to ascertain diagnostic and therapeutic information, and the inability to include case patients whose medical records were not available or whose records did not document the complaint of nocturnal leg cramps, although they had been prescribed quinine. This study was based on the treating physicians' diagnoses of nocturnal leg cramps, and misclassification by them of other types of leg pain may have occurred. This study does not provide definitive information concerning the etiologies of nocturnal leg cramps. Nevertheless, we believe this limited cohort is representative of many ambulatory veteran and other male hospital clinic patients with bothersome nocturnalleg cramps, and the results provide interesting preliminary descriptive information that may be useful in directing future studies. Results indicate that among veterans prescribed quinine sulfate, nocturnal leg cramps occur most commonly in patients older than 50. This group of patients with nocturnal leg cramps was compared with an age-matched population without nocturnal April 1997 Volume 313 Number 4
Haskell and Fiebach
leg cramps. Significantly greater numbers of medical problems were found, and they were prescribed significantly more medications than the control group. A higher incidence of neurologic and cardiovascular disease (most significantly, peripheral neurologic and peripheral vascular disease) was found in patients with nocturnal leg cramps than in the agematched controls. Although muscle cramping can occur in lower motor neuron diseases,18,19 only anecdotal reports 7,8 were found that suggested leg cramps are common in patients with nerve root compression syndromes. In this patient sample, peripheral neuropathy and radiculopathy was found to be more common in patients with nocturnal leg cramps than in the agematched control group. This suggests that peripheral neurologic injury may be associated with nocturnal leg cramps in some patients. It was reported previously that peripheral vascular disease was not a cause of nocturnal leg cramps.20 However, a general survey of rest cramps21 in a British population in 1994 found a significant association between impaired lower extremity circulation and nocturnal cramps. The higher incidence of cardiovascular disease and peripheral vascular disease in patients with nocturnal leg cramps compared with controls in this study raises the possibility that vascular disease predisposes patients to the development of nocturnal leg cramps. This association may occur because of lower extremity ischemia, disuse, atrophy, or other trophic changes; however, these possibilities remain speculative. Possibly, symptoms of claudication and rest pain are misdiagnosed as nocturnal leg cramps, increasing the apparent incidence of peripheral vascular disease in a study group of patients with cramps. Although nocturnal leg cramps are common in cancer, cirrhosis, and hemodialysis patients, these diagnoses were not common in the sample we studied. The greater degree of medical comorbidity in patients with leg cramps compared with controls in this study suggests an association with generalized debility, possibly reflecting inactivity, weakness, or poor nutritional intake as potential etiologic factors. Case patients in this study were prescribed a greater number of medications than controls. This may reflect the greater degree of medical comorbidity in patients with leg cramps, although, patients with cramps might be more "reactive" or more likely to complain of somatic symptoms than controls and therefore more likely to be prescribed more medications. Nocturnal leg cramps have been associated with the use of diuretics,4 calcium channel antagonists,5 and betaagonists. 6 Unlike previous studies, none of these medications was used more commonly in these case patients than in the control group. Because of the small size ofthe study, the possibility of an as soTHE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
ciation between these or other medications and nocturnal leg cramps cannot be excluded completely. Nitrates and tricyclic antidepressants were prescribed more to patients with nocturnal leg cramps than to controls. No other reports of any association of these medications with nocturnal leg cramps are known. We attribute the association of nocturnal leg cramps and nitrates to the confounding effects ofthe vascular disease for which they were prescribed. The significance of the association of nighttime cramps with antidepressants is not olear, especially because most were tricyclic, and tricycliclike medications, such as methocarbamol, are used as muscle relaxants. No association between leg cramps and any psychiatric diagnosis, including depression, was found. It may be that depressed patients receiving drug therapy are more likely to report and to be treated for somatic symptoms, such as cramps. A diagnostic evaluation, including physical examination or laboratory testing, was recorded in a minority of the charts of patients with nocturnal leg cramps. A possible predisposing factor for nocturnal leg cramps was identified by the patients' physicians in only 27% of the patients. This contrasts with higher estimates of specific causative factors previously reported in selected groups of patients (eg, 89% in a group of cancer patients2). Although the number of cases and controls in this study was relatively small, numerous comparisons were made between the two groups and many diseases and medications were considered. This increased the chance of a type I error in any association that was found. Although the results of all comparisons are presented with P < 0.05, those associations that are biologically plausible or consistent with previous studies and that have smaller P values (eg, the association between nocturnal leg cramps and peripheral neurologic deficit and peripheral vascular disease) are emphasized. We are inclined to regard less plausible associations with borderline P values, such as the more frequent occurrence of gastritis in patients with nighttime cramps, as a result of chance. We point out that the selection of patients based on their prescription of quinine sulfate excluded those with nocturnal leg cramps who were not treated with this therapy, possibly excluding those with less severe or persistent symptoms and those with potential contraindications to quinine (such as preexisting abnormalities ofliver function, thrombocytopenia, or cardiac disease). Some patients were excluded who were prescribed quinine but who did not have nocturnal leg cramps noted in the chart. Although the charts of these patients suggested they did not differ clinically or demographically, it is possible that these patients had less severe or less persistent symptoms. The results indicate that nocturnal leg cramps oc213
Nocturnal Leg Cramps
cur most commonly among older patients with comorbid illnesses and suggest areas for further research. Larger, controlled studies of patients with nocturnal leg cramps could assess the prevalence of peripheral neurologic and vascular abnormalities, examine the relations between cramps and functional status and disability, and reexamine more definitively the apparent lack of association of specific medications with the occurrence of nocturnal leg cramps. References 1. Baltadano, N, Gallo BV, Weidler DJ. Verapamil vs. quinine in recumbent nocturnal leg cramps in the elderly. Arch Intern Med. 1988; 148:1969-70. 2. Steiner I, Seigal T. Muscle cramps in cancer patients. Cancer. 1988;63:574-7. 3. Kaji DM, Ackad A, Nottage WG, Stein RM. Prevention of muscle cramps in hemodialysis patients by quinine sulfate. Lancet. 1976;2:66-7. 4. Physician's Desk Reference, 47th Edition. New Jersey: Medical Economics Data Production Company, 1993. 5. Zelman S. Terbutaline and muscular symptoms. JAMA. 1978; 239:930. 6. Keidar S, Binenboim C, Palant A. Muscle cramps during treatment with nifedipine. Br Med J. 1982;285:1241-2. 7. Sugar O. Causes of night cramps. JAMA. 1985;235:775-6.
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8. Rish BL. Nerve root compression and night cramps. JAMA. 1985; 254:361. 9. Young JB, Javid M, George J. Rest cramps in the elderly. Journal of the Royal College of Physicians of London. 1989;20:103-6. 10. Knochel JP. Neuromuscular manifestation of electrolyte disorders. Am J Med. 1982;72:521-5. 11. Robert HJ. Spontaneous leg cramps and "restless legs" due to diabetogenic hyperinsulinism: Observations on 131 patients. J Am Geriatr Soc. 1965; 13:602-38. 12. Araki S, Terao A, Matsumoto I, Narazaki T, Kuroiwa Y. Muscle cramps in chronic thyrotoxic myopathy. Arch Neurol. 1986; 19:315-20. 13. McGee SR. Muscle cramps. Arch Intern Med. 1990; 150:5118. 14. Lazer RB. The origin of muscle fasciculation and cramps. Muscle and Nerve. 1994; 17:1243-9. 15. Man-Son-Hing M, Wells G. Meta-analysis of the efficacy of quinine for treatment of nocturnal leg cramps in elderly people. BMJ. 1995;310:13-7. 16. Nightingale S. Quinine for nocturnal leg cramps. ACP J Club. 1995; 123(3):86-87. 17. SAS/STAT User's Guide, Release 6.03 Edition. Cary, NC: SAS Institute Inc,; 1988. 18. Mulder DW. The clinical symptoms of amyotrophic lateral sclerosis. Mayo Clin Proc. 1957;32:427. 19. Hudson AJ, Brown WF, Gilbert JJ. The muscular pain fasciculation syndrome. Neurology. 1973; 28:1105-9. 20. Cutler P. Cramps in the legs and feet. JAMA. 1984;252:98. 21. Naylor JR, Young JB. A general population survey of rest cramps. Age and Aging. 1994;23:418-20.
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