P&T News: June 1996, Vol. 16, No. 12
Barbara A. Mutnick, M.H.P.
Peer Review Status: Internally Peer Reviewed by John W.
Rachow, M.D., Assistant Professor, Director of the Geriatric Service,
Department of Internal Medicine
Overview
Nocturnal leg muscle cramps (idiopathic leg cramps) is a condition
characterized by localized, painful muscle contractions in the lower
extremities, most often the calves. The condition may begin in mid
life, but is most often experienced in elderly patients. It may also
affect younger individuals during pregnancy or patients with vascular
disease. While no regular pattern exists concerning severity,
frequency, or duration, the contractions usually occur during the
first few hours of sleep3 and disrupt sleeping patterns.
The etiology of nocturnal leg muscle cramps is not clear. Underlying medical conditions, such as liver disease, sarcoidosis, thyroid disease, and diabetes mellitus are potential causes of leg muscle cramps. Likewise, some medications that may cause leg cramps include nifedipine, terbutaline, clofibrate, nicotinic acid, diuretics, and phenothiazines.4 Restless leg syndrome (RLS) or Ekbom's syndrome is sometimes misdiagnosed or confused with nocturnal leg muscle cramps; the correct diagnosis must be made, as drug therapy differs between the two disease states.
Quinine Therapy
For a number of years, quinine sulfate has been widely used for the
treatment of nocturnal leg muscle cramps. However, clinical studies
have failed to conclusively demonstrate its effectiveness for this
indication; the subjective nature of the symptoms of nocturnal leg
muscle cramps has made it difficult for study participants to make
objective comparisons.5 In addition, there have been numerous reports
of serious and fatal adverse reactions associated with the use of
quinine for leg cramps.3 Most of the original data suggesting the
efficacy of quinine come from two studies: one was a non-controlled
study including 15 patients in 1940;6 the second was a comparison to
placebo with nine patients published in 1983.7
Later studies that compared efficacy of various agents also tended to be small in size, and did not demonstrate agreement in the therapeutic efficacy of quinine.7,12,13 The most recent attempt to sort through this confusing set of data was a meta-analysis on the data from six of these smaller, more rigorously designed studies. Criteria for inclusion were: studies that were randomized, double-blinded, placebo controlled, and cross-over in design, whose population was made up of general ambulatory (non-dialysis) patients. The cross-over design of these studies removed the differences between subjects and permitted the use of analytical techniques that increased the statistical power of the analysis. The results of this meta-analysis showed that quinine did not reduce the severity or duration of leg cramps, however; it did reduce the frequency of leg cramps.8
Adverse events associated with quinine at doses used to treat nocturnal leg muscle cramps include dizziness, fever, nausea, vomiting, diarrhea, and transient visual and auditory disturbances.9 Thrombocytopenia is a potentially fatal adverse effect of quinine. Other severe adverse effects occurring at high quinine levels (cinchonism) include nausea, vomiting, tinnitus, deafness, headache, unsteady gait, and visual disturbances. Rarely seen adverse effects include blindness, seizure, coma, arrhythmias, hypotension, and death.3,7,9 Quinine has also been implicated in several potentially dangerous drug-drug interactions, most notably due to its ability to elevate serum digoxin levels.10 Recent data demonstrate that quinine also elevates astemizole levels which may result in QT interval prolongation."
The recommended dose of quinine in the treatment of nocturnal leg muscle cramps is 260 to 300 mg taken at bedtime. If necessary, an additional dose may be taken with the evening meal. For patients receiving quinine, comprehensive medication counseling regarding potential adverse effects and their heralding signs and symptoms should be conducted.
Other Treatment Options
Other therapies that have been investigated for the treatment of
nocturnal leg muscle cramps include vitamin E,12 carisoprodol
(Soma® ,13 chloroquine phosphate,14 and verapamil.9
Vitamin E was initially tried for nocturnal leg muscle cramps following a dermatologist's observation that a patient taking vitamin E for other indications had improvement in his nocturnal leg muscle cramps.'5 There are two uncontrolled series of cases with patients taking vitamin E 300 to 400 IU per day. The first study reported that 82% (103/125) of the patients achieved "excellent" control of their nocturnal leg muscle cramps from these doses.'5 The second report is stated in a letter to the editor and asserts that "the medication is almost universally effective" for more than 100 patients treated with 300 IU daily.16 However, a recent crossover trial, which was included in the previously mentioned meta- analysis study, used 27 patients to compare vitamin E to quinine and placebo; only quinine (500 mg daily) was found to be superior to placebo in reducing leg cramp frequency, severity, and incidence of sleep disturbance. Vitamin E was not found to be superior to placebo.12
Most of the data for the other therapies come from single reports published in the 1960s. A double- blind, placebo-controlled trial found carisoprodol dosed at 350 mg four times a day caused improvement in cramping in 21 of 26 patients.l3 Chloroquine phosphate 250 mg given daily was shown to reduce the frequency and/or severity of cramping in a double-blind, placebo-controlled study with 19 patients.'4 The investigators identified no acute adverse effects over the course of the nine- week study; however, due to the risk of retinal degeneration from chloroquine, this drug should be reserved for treatment of severe cases, provided close ophthalmologic monitoring is conducted.
More recently, seven of eight patients given verapamil 120 mg at bedtime were shown to have decreased cramping, usually within six days of initiation of therapy. All patients in this study had been taking quinine prior to enrollment, but had been refractory to quinine therapy.'7 The potential for adverse affects secondary to calcium channel blocking agents (e.g., nocturnal hypotension) may preclude its use in a large proportion of patients.
Currently, first-line therapy for nocturnal leg muscle cramps continues to be non-pharmacologic interventions. These include: massaging the legs, prophylactic gastrocnemius muscle stretching before retiring, hot soaks, moderate exercise (walking), elevating the foot of the bed, binding the legs in constrictive wrappings, and emptying the bladder before going to bed.'
Conclusion
Clearly, more carefully controlled studies are needed in order to
document the actual clinical safety and efficacy of quinine and other
pharmacologic agents in the treatment of leg muscle cramps. In light
of the FDA's ruling regarding the lack of efficacy and safety in OTC
quinine products and the lack of good clinical data supporting other
pharmacologic therapies for treatment of nocturnal leg muscle cramps,
nonpharmacological modalities should be utilized.
References
Drugs Added to Stock
AMPHOTERICIN B LIPID COMPLEX Injection: 5 mg per ml, 20 ml vial Amphotericin B lipid complex injection (Abelcet® -Liposome) is indicated for the treatment of aspergillosis in patients who are refractory or intolerant of conventional amphotericin B therapy. Efficacy data for other fungal pathogens are currently lacking. [NOTE: Amphotericin B lipid complex is a protocol drug restricted to: 1) documented aspergillosis infection by culture, histology, or appropriate imaging studies and refractory to conventional amphotericin B treatment of greater than or equal to l gram; 2) intolerant of conventional amphotericin B and not a candidate to receive other appropriate antifungals; or 3) Infectious Diseases consult obtained.]
ANASTROZOLE Tablets: 1 mg Anastrozole (Arimidexd® - Zeneca) is a nonsteroidal aromatase inhibitor indicated for the treatment of advanced breast cancer in postmenopausal women with disease progression following tamoxifen therapy.
CISATRACURIUM Injection: 2 mg per ml Cisatracurium (Nimbext® - GlaxoWellcome) is a nondepolarizing neuromuscular blocking agent indicated as an adjunct to general anesthesia, to facilitate tracheal intubation, and to provide skeletal muscle relaxation during surgery or mechanical ventilation in the intensive care unit.
COLLAGENASE Topical Ointment: 250 units per gram Collagenase (Santyl® - Knoll) is an enzymatic debriding agent. It is a replacement product for sutilains (Travase® ) which has been discontinued by the manufacturer.
DESMOPRESSIN ACETATE Tablets: 0.1 mg and 0.2 mg Desmopressin (DDAVP® - Rhone-Poulenc Rorer) acetate oral tablets are indicated for antidiuretic replacement therapy in the management of central diabetes insipidus and the management of temporary polyuria and polydipsia following head trauma or surgery in the pituitary region.
RESPIRATORY SYNCYTIAL VIRUS IMMUNE GLOBULIN Injection: 50 mg per ml, 50 ml vial. Respiratory syncytial virus immune globulin injection (RSV-IG, Respigam® - Medimmune) is indicated for the prevention of serious lower respiratory tract infection caused by RSV in children less than 24 months of age with bronchopulmonary dysplasia or a history of premature birth . [NOTE: RSV-IG is protocol drug restricted to prophylactic use in: 1) infants less than 2 years of age who have both chronic lung disease and a cardiac lesion with left-to-right shunting (e.g., atrial septal defect, ventricular septal defect, patent ductus arteriosus); 2) infants less than 1 year of age who require home oxygen at 1/2 liter per minute or more; or 3) infants less than 6 months of age who require home oxygen at 1/4 liter per minute or more. Due to lack of data supporting the use of RSV-1G for treatment of RSV disease, use of the drug for treatment will be considered heroic drug therapy and require approval as by the Chair of the Pharmacy and Therapeutics Subcommittee or his delegate.]
Additional Actions
AMOXICILLIN/CLAVULANATE (Augmentin® TABLETS The 875 mg strength (875 mg amoxicillin and 125 mg clavulanate) has been added to stock. It is designed to be dosed on a twice daily regimen, thereby increasing patient compliance.
HEPATITIS A VACCINE (Havriix® ) Injection: 720 EL.U. per 0.5 ml This strength has been added to stock. Primary immunization of children (2 through 18 years of age) requires only two doses of vaccine (initial and a booster 6 to 12 months after the initial dose) with this formulation versus three doses of vaccine (initial, one month later, and a booster 6 to 12 months after the initial dose) with the 360 EL.U. per 0.5 ml formulation.
LEUPROLIDE ACETATE Injection: 22.5 mg per vial This 3-month depot injection of leuprolide acetate (Lupront® Depot - 3 Month) has been added to stock. The 3-month formulation is indicated for the palliative treatment of advanced prostatic cancer.
PAROXETINE TABLETS (Paxil® ) The 10 mg and 40 mg tablets were added to stock.
SOMATROPIN Injection: 5 mg per ml, 2 ml vial Somatropin in a ready-to-use aqueous formulation (Nutropin AQ® ) has been added to stock. It will replace the Iyophylized powder (Nutropin® ) for injection.
Drugs Deleted From Stock
ALUMINUM CHLORIDE HEXAHYDRATE (Xerac AC® ) Deleted due to low use.
ANTHRALIN 1% OINTMENT (Anthrnderm® ) Deleted due to low use. Anthralin 0.5 % ointment is available.
BLADDER MIXTURE WITH PHENOBARBITAL Discontinued due to low use. Bladder mixture without phenobarbital is available.
COAL TAR OINTMENT 1.5% IN AQUAPHILIC OINTMENT AND WHITE PETROLATUM Deleted due to low use. Coal tar ointment I .5 % in aquaphilic ointment is available.
COLLAGEN BOVINE (Zyderm® I Implant) INJECTION Discontinued due to low use. Zyderm0 n Implant and Zyplast0 Implant are available.
CROTAMITON 10% AND BETAMETHASONE 0.1% CREAM Deleted due to low use.
CROTAMITON 10% (Eura® ) LOTION Deleted due to low use. Permethrin 5 % Cream (Elimite® ) is available.
DEXAMETHASONE 0.25 MG TABLETS Discontinued by the manufacturer. Dexamethasone oral liquid and 0.5 mg tablets are available.
8-METHOXYPSORALEN (8-MOP) CAPSULES Deleted due to low use. Methoxsalen is available.
FAT EMULSION 30% INTRAVENOUS INJECTION Deleted due to duplication with other stocked products. Fat emulsion 20% and 10% intravenous injections are available.
HEPATITIS A VACCINE (Havrix® ) 360 EL.U. per 0.5 ML INJECTION Replaced with 720 EL.U. per 0.5 ml injection which requires fewer doses for complete immunization.
POTASSIUM PERCHLORATE CAPSULES Deleted due to low use. Alternate diagnostic tests are available.
SODIUM BICARBONATE 1 GRAM CAPSULES No commercial source. Sodium bicarbonate 650 mg tablets are available.
SOMATROPIN (Nutropin® ) POWDER FOR INJECTION Replaced with a ready-to-use aqueous formulation (Nutropin AQ® ).
SUTILAINS (Travase® ) OINTMENT Discontinued by the manufacturer. Collagenase (Santyl® ) is available.
ZINC OXIDE TOPICAL BANDAGE (Dome Paste® Bandage, Unna's Boot) Transferred to Processed Stores.