Treatment of leg cramps in patients with chronic kidney disease receiving hemodialysis.
After reading this article, the reader will be able to:
* Describe factors that contribute to leg cramps for patients receiving hemodialysis
* Compare and contrast the pharmacologic interventions to treat leg cramps
* Discuss non-pharmacologic interventions to treat leg cramps.
Muscle cramps (involuntary muscle contraction associated with severe pain) occur frequently in patients receiving dialysis. Muscle cramps can involve the legs, most commonly in the feet, but can also involve arms and hands, as well as abdominal muscles (Holley, 2011; Kobrin & Berns, 2007). It is estimated that 33% to 86% of patients receiving dialysis have experienced cramps (Holley, 2011). In a study from 2001, 25% of hemodialysis patients reported two or more interdialytic cramps weekly (Khajehdhi, Mojerlou, Behzadi, & Rais-Jalali, 2001). The purpose of this paper is to review medications used to treat muscle cramps in patients with chronic kidney disease (CKD) receiving hemodialysis.
Pathophysiology and associated medical conditions
Muscle cramps begin with fasciculations or muscle twitches and are felt to be related to nerve conduction rather than the muscles themselves (Holley, 2011). Numerous factors contribute to muscle cramps in patients with CKD receiving dialysis and include volume contraction, hypotension, changes in plasma osmolality, hyponatremia, tissue hypoxia, hypomagnesemia, deficiency of carnitine and elevated serum leptin (Holley, 2011; Kobrin & Berns, 2007). Patients who experience cramps associated with dialysis have been reported to have lower parathyroid hormone levels than patients who do not experience cramps (Holley, 2011). Low concentrations of sodium in the dialysate bath and increased ultrafiltration required to remove excess fluid are factors related to the dialysis procedure itself, which increase the risk of muscle cramps (Holley, 2011).
Muscle cramps may have serious consequences for patients who experience them. Muscle cramps can be painful and this may impact quality of life. Cramps may also limit a patient's ability to tolerate dialysis and, therefore, contribute to underdialysis or chronic fluid overload. Patients who experience cramps associated with dialysis have been reported to have higher serum creatine phosphokinase values (suggesting muscle injury) than patients who do not experience cramps (Holley, 2011).
Quinine is a medication that has been used for many years for the treatment of cramps both in the general population and in the dialysis population (Kobrin & Berns, 2007). Quinine is approved only for the treatment of malaria, and is used off-label to treat cramps. Quinine reduces leg cramps by decreasing excitability of the nerve stimulations, which increases the muscle refractory period and, subsequently, prevents prolonged muscle contractions (Canzanello & Burkhart, 1992). Quinine does not require a dose reduction for reduced renal function, but has a delayed onset of action, so it must be administered one to two hours prior to starting hemodialysis (Kobrin & Berns, 2007).
Some evidence from clinical trials supports the common practice of using quinine for leg cramps in patients without CKD or in those receiving dialysis. A systematic review of 23 trials (1,586 patients) found that quinine 300 mg daily (range 200 mg to 500 mg) reduced cramp number over two weeks by 28%, cramp intensity by 10% and cramp days by 20%. Cramp duration was not affected. In the included trials, there were no significant differences in adverse effects compared to placebo, with only one quinine-treated patient experiencing thrombocytopenia. The authors concluded that therapy with quinine up to 60 days was supported by moderate quality evidence, and with this duration of therapy, serious adverse events did not appear to be different from placebo (El-Tawil, Musa, Valli, Lunn, El-Tawil, & Weber, 2010). However, this systematic review included only two studies with dialysis patients (Kaji, Ackad, Nottage, & Stein, 1976; Roca et al., 1992).
Very little evidence from clinical trials supports the common practice of using quinine for leg cramps in patients receiving dialysis (Kaji, Ackad, Nottage, & Stein, 1976; Sandoval et al., 1980; Roca et al., 1992). In the first published randomized study, nine hemodialysis patients with frequent cramps (baseline rate not specified) received 320 mg quinine or placebo before each dialysis session for 12 weeks. Over 162 dialysis sessions, patients receiving quinine experienced cramps during 6.2% of dialysis sessions, compared with 17.3% of those taking placebo (Kaji, Ackad, Nottage, & Stein, 1976). However, this study was of short duration, and did not measure the number of cramps or intradialytic cramps (El-Tawil, Musa, Valli, Lunn, El-Tawil, & Weber, 2010). In the second study of eight patients who received 300 mg quinine for eight weeks followed by placebo for eight weeks, the frequency of cramps was reported to be reduced (Sandoval et al., 1980). However, this study was not included in the systematic review, because it was not randomized and patients were also treated with hypertonic saline (El-Tawil, Musa, Valli, Lunn, El-Tawil, & Weber, 2010). In a third study, 29 patients receiving hemodialysis were prescribed quinine 325 mg daily (16 patients) or vitamin E 400 IU daily (13 patients) for two months. Quinine reduced leg cramps to 3.3 per month, and vitamin E to 3.6 per month (p-----0.005 for both groups), and both treatments reduced pain severity (Roca et al., 1992). However, this study did not report on adverse effects and only reported outcomes for 30 of the 60 days of treatment (El-Tawil, Musa, Valli, Lunn, El-Tawil, & Weber, 2010).
Numerous reports of toxicity related to quinine have recently been cause for concern. Adverse effects of quinine include tinnitus, deafness, dizziness, nausea and vomiting (generally after consumption of toxic amounts), cardiac arrhythmias, thrombocytopenia, hypersensitivity reactions and hemolytic uremic syndrome (Kobrin & Berns, 2007). Many of these serious adverse reactions, especially profound thrombocytopenia, can occur at any time during therapy, even after a single dose (Brinker & Beitz, 2002; Younger-Lewis, 2011). Quinine also has several important drug interactions, including with warfarin and digoxin (Kobrin & Berns, 2007). Recently, the Food and Drug Administration in the United States has issued warnings about using quinine for the treatment of leg cramps, and cautioned consumers and prescribers that the risk of severe adverse events does not justify the use of quinine for this indication (U.S. Food and Drug Adminstration, 2010). Prescribers in the United States are now required to provide patients with information about the risk of potentially severe reactions, as part of a risk management plan (U.S. Food and Drug Adminstration, 2010). Similarly, Health Canada published a review of 71 reports of serious adverse reactions suspected to be associated with quinine (thrombocytopenia, Stevens-Johnson syndrome, vasculitis, arrhythmia); 41 of these were life-threatening or required the patient to be hospitalized. Health Canada reminds health professionals about the severity of adverse effects associated with quinine, and that quinine is not indicated for the treatment of leg cramps (Younger-Lewis, 2011).
Three studies suggest that vitamin E may be an alternative therapy for the management of leg cramps for patients receiving dialysis. One small study discussed above found similar reduction in leg cramps between quinine and vitamin E (Roca et al., 1992). In another study, 60 hemodialysis patients with a mean of 4.4 cramps per week were randomized to receive vitamin E 400 IU daily, vitamin C 250 mg daily, a combination, or placebo for eight weeks. The mean number of cramps per week decreased by 54%, 61%, 97% and 7% for the vitamin E, vitamin C, combination and placebo groups respectively, and no adverse effects were reported (Khajehdehi, Mojerlou, Behzadi, & Rais- Jalali, 2001). Finally, a study of 19 hemodialysis patients with a mean number of cramps over a 12-week period of 77.1 (6.4 cramps per week) received vitamin E 400 IU daily for 12 weeks. The mean number of cramps declined over a second 12-week period to 24.8 (2.1 cramps per week), with no adverse effects (El-Hennawy & Zaib, 2010). Both studies were of short duration, and one study was not blinded, had no control group and was not randomized. It is unclear if any adverse effects would result from dialysis patients continuing to take vitamin E with or without vitamin C therapy long-term. Vitamin E is known to cause bleeding, and to interact with warfarin to increase the risk of bleeding (Product monograph, vitamin E). Additionally, a meta analysis of 19 clinical trials with 135,967 participants in studies of vitamin E found that high-dosage (> or = 400 IU/d) vitamin E increased all-cause mortality (Miller, Pastor-Barriuso, Dalal, Riemersma, Appel, & Guallar, 2005). It is recommended that vitamin C supplementation be limited to 60 mg to 100 mg daily. Higher doses can result in the accumulation of a metabolite of vitamin C called oxalate. High levels of oxalate in the blood may lead to the development of kidney stones composed of calcium oxalate and in calcium oxalate deposits in organs, soft tissues, joints and blood vessels. (Rocco & Blumenkrantz, 2000). Replavite[R], a multivitamin commonly prescribed for dialysis patients, contains 100 mg of vitamin C.
Carnitine deficiency is felt to contribute to the pathophysiology of muscle cramps, which has led to several studies of its effect on cramps. A meta-analysis of six randomized, placebocontrolled trials with 167 hemodialysis patients that evaluated the effect of levocarnitine on cramps found a pooled odds ratio of 0.3 (0.009-1.00, p=0.05), suggesting, although not statistically significant, that carnitine may improve cramps. However, these studies were of varying duration and of heterogeneous design, with the seeming benefit driven by a single positive study. When the analysis was limited to studies conducted with modern dialysers (1990 or later), or all the studies except the outlier study, the results became clearly non-significant, suggesting no benefit to supplementation with carnitine (Lynch, Feldman, Berlin, Flory, Rowan, & Brunelli, 2008). A Japanese supplement of peony and liquorice root (shakuyaku-kanzo-to) administered to patients with cramps has demonstrated efficacy in treating 61 dialysis patients; cramps were relieved in an average of 5.3 minutes in 54 or 61 cases (Hyodo et al., 2006). However, the study was not blinded, had no control group, and was not randomized. Additionally, the ultrafiltration rate was reduced during cramps, so any effect of the medication is not known (Kobrin & Berns, 2007). Well designed placebocontrolled trials are required before carnitine or shakuyakukanzo- to can be offered as therapeutic alternatives for patients receiving dialysis.
Numerous strategies can be employed in order to prevent cramps in patients receiving dialysis. The most common factors related to the hemodialysis procedure itself are volume contraction and hyponatremia. Preventing hypotension associated with dialysis, minimizing interdialytic weight gains including reevaluating the patient's appropriate dry weight, the use of sodium modelling, increasing the frequency of hemodialysis, or switching to peritoneal dialysis have been effective in reducing the frequency of cramping. Local massage of the affected muscle and the application of moist heat may provide some comfort. Other low-risk strategies include performing stretching exercises before dialysis, performing mild exercise such as riding a stationary bicycle during dialysis or prior to bedtime, minimizing alcohol and caffeine, and keeping bed covers loose and not tucked in to prevent cramps. Local heat (including showers or baths) or ice, massage, walking or leg jiggling followed by leg elevation, are other methods reported to help relieve muscle cramps (Holley, 2011; Sheon, 2011).
If cramps occur during dialysis, it is important to assess the patient for hypotension. Dialysis-related hypotension may be treated through slowing or stopping ultrafiltration, placing a patient in Trendelenberg position, or reducing the blood flow rate. Hypertonic saline or 50% dextrose may be useful for the treatment of dialysis-associated cramps occurring near the end of dialysis. These treatments were shown to be equally effective for the relief of cramps in a double-blind, placebocontrolled study of 20 patients with 100 episodes of muscle cramps (Holley, 2011; Sherman, Goodling, & Eisinger, 1982). However, hypertonic (50%) dextrose has been suggested to be the better therapeutic option in non-diabetic patients because it does not adversely affect salt and water balance. Mannitol infusions are not recommended over hypertonic saline or 50% dextrose, especially near the end of a hemodialysis session, as mannitol may accumulate in the extracellular space.
Implications for practice
It is important to discuss non-pharmacologic strategies to prevent and treat muscle cramps with patients in order to minimize pharmacotherapy and to utilize hemodialysis interventions such as sodium modelling and reassessing dry weight. The literature describing effective pharmacotherapeutic interventions to prevent muscle cramps in patients with chronic kidney disease is lacking. Patient education about the available evidence for benefit and potential for harm of pharmacotherapy, is an important aspect of treatment. If a trial of quinine is considered, patients should be apprised of the potential for harm associated with the therapy. Some references suggest informed consent. Careful monitoring of the patient for efficacy and toxicity are warranted; if the drug is ineffective, or if any evidence for adverse effects, it should be discontinued (Kobrin & Burns, 2007). A short-term trial of vitamin E can be considered. However, interactions with antiplatelets, anticoagulants, and a concern for adverse effects for patients at risk of bleeding may limit its use in dialysis patients. For patients who receive these therapies, an evaluation of quinine or vitamin E prescriptions for a potential to discontinue is important to minimize toxicity related to medications.
The efforts of Laura Delavau, pharmacy student, University of Manitoba, in performing a drug information search on this topic are acknowledged.
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By Colette B. Raymond, PharmD, MSc, and Lori D. Wazny, PharmD
Colette B. Raymond, PharmD, MSc, Clinical Pharmacist, Winnipeg Regional Health Authority, Manitoba Renal Program, Winnipeg, MB.
Lori D. Wazny, PharmD, Clinical Pharmacist, Winnipeg Regional Health Authority, Manitoba Renal Program, Winnipeg, MB.
Address correspondence to: Colette Raymond, PharmD, Department of Pharmaceutical Services, Health Sciences Centre Hospital, MS189-820 Sherbrook St., Winnipeg, MB R3A 1R9
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|Title Annotation:||CONTINUING EDUCATION SERIES|
|Author:||Raymond, Colette B.; Wazny, Lori D.|
|Date:||Jul 1, 2011|
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