Assessment: Symptomatic treatment for muscle cramps (an evidence-based review)
Transcription
Assessment: Symptomatic treatment for muscle cramps (an evidence-based review)
SPECIAL ARTICLE Assessment: Symptomatic treatment for muscle cramps (an evidence-based review) Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology Hans D. Katzberg, MD Ahmir H. Khan, MD Yuen T. So, MD, PhD Address correspondence and reprint requests to American Academy of Neurology, 1080 Montreal Ave., St. Paul, MN 55116 [email protected] ABSTRACT Background: A Food and Drug Administration advisory in 2006 warned against the off-label use of quinine sulfate and its derivatives in the treatment of muscle cramps. Physicians are faced with a difficult scenario in choosing a treatment regimen for patients with muscle cramps. This American Academy of Neurology assessment systematically reviews the available evidence on the symptomatic treatment of muscle cramps. Methods: A total of 563 potential articles were reviewed, of which 24 met the inclusion criteria of prospective trials evaluating the efficacy of a particular treatment on muscle cramps as a primary or secondary outcome. Results: There are Class I studies showing the efficacy of quinine derivatives for treatment of muscle cramps. However, the benefit is modest and there are adverse effects from published prospective trials as well as case reports. There is one Class II study each to support the use of Naftidrofuryl, vitamin B complex, lidocaine, and diltiazem in the treatment of muscle cramps. Recommendations: Although likely effective (Level A), quinine derivatives should be avoided for routine use in the management of muscle cramps because of the potential of toxicity, but in select patients they can be considered for an individual therapeutic trial once potential side effects are taken into account. Vitamin B complex, Naftidrofuryl, and calcium channel blockers such as diltiazem are possibly effective and may be considered in the management of muscle cramps (Level C). Further studies are needed to identify agents that are effective and safe for the treatment of muscle cramps. Neurology® 2010;74:691–696 GLOSSARY ALS ⫽ amyotrophic lateral sclerosis; CI ⫽ confidence interval; FDA ⫽ Food and Drug Administration. Muscle cramps are involuntary, generally painful contractions of a muscle or muscle group. Some patients are bothered by very frequent and severe muscle cramps that may be disabling. A cross-sectional prevalence study of 365 outpatients aged 65 or older in the United Kingdom reports that 50% of outpatients report frequent cramps.1 Another review of 515 elderly veterans reports a similar prevalence of 56%, with half having cramps occurring at least once per week.2 When the motor system is stressed, either by a neuromuscular disease or by a physiologic stress such as dehydration or excessive exercise, cramps become more frequent. Muscle cramps are caused by ectopic discharges from nerves or nerve terminals3; therefore, a variety of neuropathic conditions such as amyotrophic lateral sclerosis (ALS), peripheral neuropathies, and cramp-fasciculation syndrome are commonly associated with cramps.4 In addition to neurologic conditions, multiple medical conditions such as hypomagnesemia, hypocalcemia, hypothyroidism, and renal or liver dysfunction may be the cause of cramps. Cramps are also frequent during the last trimester of pregnancy and in athletes such as marathon runners.5,6 When no underlying cause of recurrent muscle cramps can be identified, they are referred to as idiopathic muscle cramps, which can be variable in presentation from patient to patient but are usually most prominent in the lower leg and foot muscles and more evident at night. Since early reports in the 1930s and 1940s,7 quinine and its derivatives have been the mainstay of Supplemental data at www.neurology.org From the Stanford University School of Medicine, Palo Alto, CA. Appendices e-1 through e-4 and table e-1 are available on the Neurology® Web site at www.neurology.org. Approved by the Therapeutics and Technology Assessment Subcommittee on April 28, 2009; by the Practice Committee on July 1, 2009; and by the AAN Board of Directors on November 9, 2009. Disclosure: Author disclosures are provided at the end of the article. Copyright © 2010 by AAN Enterprises, Inc. 691 therapy for idiopathic muscle cramps. However, a United States Food and Drug Administration (FDA) Federal Register statement released on December 15, 2006, ordered unapproved quinine drugs to be removed from the market and cautioned consumers about their “off-label” use, citing “665 reports of adverse events with serious outcomes associated with quinine use, including 93 deaths” since 1969.8 Quinine sulfate, in particular Qualaquin®, is the only FDA-approved drug for the treatment of plasmodium falciparum malaria. Use of the drug for any other indication, including muscle cramps, is unapproved. In addition to quinine, a number of other agents have been studied in the treatment of muscle cramps, including antiepileptics, calcium channel blockers, and various vitamins, supplements, and minerals. This assessment addresses the available evidence on the efficacy as well as possible adverse effects of symptomatic treatment of idiopathic muscle cramps. DESCRIPTION OF THE ANALYTIC PROCESS The main search strategy was a comprehensive search of MEDLINE and EMBASE from 1950 to May 31, 2008, using the search term “muscle cramp” limited to keywords “therapy,” “drug therapy,” and “prevention and control,” which yielded 558 results in 4 languages (including French, German, Spanish, and English). Additional articles were identified by crossreferencing bibliographies from meta-analyses, review articles, and case reports identified in the initial search, which yielded 5 additional articles. “Muscle cramp” was defined as a sustained, generally painful, involuntary contraction of a muscle or muscle group. “Cramps” alone was not used as a search term due to excessive articles on gynecologic and gastrointestinal cramps. The abstracts and titles from the 563 articles identified were reviewed, and a study was included if it was a prospective clinical trial with effect on muscle cramps as a primary or secondary outcome. Exclusion criteria were 1) review articles, 2) meta-analyses, 3) case reports or case series that did not involve a treatment, 4) phenomena not consistent with muscle cramps, such as muscle spasms, dystonia, or muscle pains, 5) pregnancy-induced cramps, 6) medical conditions such as hemodialysis and cirrhosis, and 7) cramps due to extreme physiologic stress such as excessive exercise, heat, or dehydration. Cramps secondary to medical conditions were excluded from this analysis because the mechanisms underlying the formation of cramps and often the treatment directed to correct them are distinct from the routine treatment of muscle cramps, and most treatment tri692 Neurology 74 February 23, 2010 als assessing idiopathic cramps also excluded these conditions. Muscle cramps due to myopathies were also excluded due to the distinct underlying mechanisms. Articles excluded after initial review of the 563 titles and abstracts included 13 articles on hemodialysis, 6 articles on cirrhosis, 4 articles on physiologically induced cramps, 11 articles on pregnancy, 39 review articles, and 10 case reports without treatments (total 63 articles). Upon further review, 450 articles were excluded as they were letters or types of publications other than clinical trials or did not deal with muscle cramps or therapy. A total of 50 potential studies were identified for full review. Full review of the articles led to further exclusion of 26 articles that were review articles, letters, or repeat publications of the same clinical trials. The remaining 24 articles were chosen for inclusion in the final review, including one article dealing with nonpharmacologic therapy, 5 open-label pharmacologic trials, and 18 randomized pharmacologic trials. The final 24 articles involving symptomatic treatment of cramps were distributed to all 3 panel members for critical analysis and classification. Each member of the panel made an independent determination of class of evidence and a final meeting was called to discuss the articles and resolve differences. Data regarding cohort size, completion rate, inclusion and exclusion criteria, treatment and dosage, design of the study, length of study, primary and secondary outcomes, efficacy, and effect size were extracted from each article and tabulated (table e-1 on the Neurology® Web site at www.neurology.org). Each article was classified according to the American Academy of Neurology therapeutic classification of evidence scheme (appendix e-3) and recommendations were based on the level of evidence (appendix e-4). ANALYSIS OF EVIDENCE Question 1: Are there effective nonpharmacologic treatments for muscle cramps? Many nonpharmacologic therapies are em- ployed by patients prior to prescription treatment, but there is little evidence to support the use of any of them. Hydration, particularly for exercise-associated cramping, is frequently used by patients; however, there are no formal studies supporting its use. An open-label (Class IV) study from 1979 suggested that stretching affected muscles 3 times a day could reduce cramping.9 A randomized Class II study of 191 patients compared patients who stretched their calves 3 times a day to patients instructed in a sham exercise that involved moving the legs without stretching and found no benefit of stretching on the frequency of cramps or number of cramp-free nights.10 This trial was limited because it had acknowledged difficulties maintaining good patient blinding, and the control patients were given sham exercises that could theoretically provide some benefit. Conclusion. Data are insufficient to draw any conclusion on the efficacy of calf stretching in reducing the frequency of muscle cramps. Recommendation. None (Level U). Question 2: Is quinine effective in the treatment of muscle cramps? Thirteen studies were found involv- ing quinine or quinine derivatives: 2 Class I studies showing efficacy,11,12 4 Class II studies (2 showing efficacy and 2 showing lack of efficacy),13-16 5 Class III studies (2 showing efficacy and 3 showing lack of efficacy),17-21 and 1 Class IV study showing efficacy.22 Only the Class I and II studies are discussed below. Class I studies. A randomized trial in 1997 assessed the efficacy of hydroquinine hydrobromide dihydrate 300 mg at night in 112 patients.11 The trial showed a greater reduction in median number of cramps in treated patients compared to placebo (5 fewer cramps, 95% confidence interval [CI] 2– 8 cramps) and a reduction of cramp days in treated patients compared to placebo (1 fewer cramp day, 95% CI 0 –3 cramp days) during the 3-week study period. The mean number of cramps was reduced by 37%. Another Class I study (n ⫽ 109) using 400 mg of quinine showed a modest though significant reduction in the median number of cramps between the run-in and treatment phases (8 cramps, 95% CI 7–10 cramps vs 6 cramps, 95% CI 3–7 cramps).12 The median number of cramps was reduced by 25%. One criticism of this trial was the restrictive inclusion criteria, which excluded patients above age 70 (who are often the patients with difficult-to-treat muscle cramps). Class II studies. All 4 Class II studies involved small cohorts (20 – 43 patients) and none addressed sample size and power calculation.13-16 Two showed efficacy but were limited by inadequate description of baseline characteristics of the treatment and placebo groups,13,14 which does not allow for a fair comparison between the groups and does not control for the potential of inadequate randomization. A trial published in 1994 showed a significant decrease in the mean number of cramps in the group treated with hydroquinine hydrobromide 300 mg in the treatment phase compared to the run-in phase (16.1 cramps, SD 14.7 cramps), whereas the placebo group did not (5 cramps, SD 16.3 cramps).13 A second Class II study found a significant reduction in the mean number of cramps from 44 in the run-in phase to 19.2 ⫾ 5.3 in the treatment group (500 mg quinine sulfate at night) and from 44 to 36.6 ⫾ 6.6 in the placebo group ( p ⫽ 0.0046). There were also beneficial effects on the number of nights with cramps and sleep disturbance.14 Two other Class II studies were limited by poor patient compliance and low completion rates of 52% and 70%.15,16 Neither showed a significant effect of quinine sulfate (200 –300 mg qhs quinine sulfate) on frequency or intensity of muscle cramps. Adverse effects of quinine and its derivatives. Common and serious side effects reported in the literature as case reports or series as well as all side effects identified in the 13 studies are listed in the table. A total of 10 minor and 11 serious side effects were identified; the most consistently reported minor side effects were cinchonism (headache and tinnitus) and bitter taste. The most common serious side effects reported were hematologic abnormalities such as hemolytic uremic syndrome–thrombotic thrombocytopenia purpura, disseminated intravascular coagulation, and bleeding diathesis. There were no reports of cinchonism leading to deafness. The frequency of any serious side effect from the studies published in this review was 2% to 4%. We did not find any reports of fatalities from quinine sulfate in any of the studies reviewed in this article. A recent FDA statement reports 93 fatalities and 663 serious adverse events related to quinine; however, no details regarding these events are available for general review.8 Although inclusion of all references for case reports is outside the scope of this article, an article that overviews the majority of common and serious side effects of quinine is referenced here.23 Conclusion. On the basis of data from 2 Class I studies, quinine derivatives are effective in reducing the frequency of muscle cramps, although the magnitude of benefit is small. Moreover, these agents are associated with serious though uncommon side effects. Recommendation. Although likely effective (Level A), the use of quinine derivatives for treatment of muscle cramps should be avoided for routine treatment of cramps. These agents should only be considered when cramps are very disabling, no other agents relieve symptoms, and there is careful monitoring of side effects. They should only be used after informing the patient of the potentially serious side effects. Question 3: Are there any other pharmacologic treatments effective for the treatment of muscle cramps? Class I studies. A double-blind randomized con- trolled trial of 3,600 mg per day of gabapentin in 204 patients with ALS evaluated muscle cramps (among other symptoms such as fasciculations, stiffness, sleeping, and emotionality) using a severity score from 0 to 10 and found no difference between treatment and placebo with respect to any symptom score.24 Class II studies. A Class II study of 28 patients in 1998 showed that vitamin B complex (including 30 mg per day of vitamin B6) induced remission of muscle cramps in 86% of treated patients who were not known to be vitamin deficient compared to plaNeurology 74 February 23, 2010 693 Table Reported side effects in case reports and prospective trials using quinine sulfate or derivatives Risk Exposure Class (reference) SER Typical dosage (300 mg PO qhs) IV 1/49 (2%) 300 mg hydroquinine/day I (11) 1/23 (4%) 200 mg quinine sulfate qhs II (16) Hypoglycemia SER Typical dosage (300 mg PO qhs) IV Vision loss (retinal toxicity) SER Typical dosage (300 mg PO qhs) IV Hepatotoxicity SER Typical dosage (300 mg PO qhs) IV Cardiac arrhythmias SER Typical dosage (300 mg PO qhs) IV 1/49 (2%) 300 mg hydroquinine/day I (11) Acute pulmonary edema SER Typical dosage (300 mg PO qhs) IV Acute hypersensitivity reaction SER Typical dosage (300 mg PO qhs) IV 1/30 (3%) 500 mg/day, mention rest of rxns not doc II (14) Psychosis SER Typical dosage (300 mg PO qhs) IV Abortion SER Typical dosage (300 mg PO qhs) IV Esophagitis SER Typical dosage (300 mg PO qhs) IV SER Typical dosage (300 mg PO qhs) IV Side effects Serious HUS-TTP with DIC, HUS-TTP with acral necrosis, pancytopenia, thrombocytopenia, bleeding diathesis Minor Photosensitivity reactions, blurry vision Cinchonism 1/8 (12.5%) 200 mg quinine sulfate qhs II (17) SER Typical dosage (300 mg PO qhs) IV 1/8 (12.5%) 200 mg quinine sulfate qhs II (17) 1/49 (2%) 300 mg hydroquinine/day I (11) 1/47 (2%) 400 mg quinine sulfate/day I (12) Hyperpigmentation, lichen planus SER Typical dosage (300 mg PO qhs) IV Bitter taste, dry mouth 10/49 (20%) 300 mg hydroquinine/day I (11) 3/20 (15%) Hydroxyquinine hydrobromide 300 mg qhs II (13) 10/49 (20%) 300 mg hydroquinine/day I (11) 1/20 (5%) Hydroxyquinine hydrobromide 300 mg qhs II (13) Headache 5/49 (10%) 300 mg hydroquinine/day I (11) Dizziness 3/49 (6%) 300 mg hydroquinine/day I (11) 1/23 (4%) 200 mg quinine sulfate qhs II (16) Tremor 2/49 (4%) 300 mg hydroquinine/day I (11) Itching 2/49 (4%) 300 mg hydroquinine/day I (11) Tingling 1/20 (5%) Hydroxyquinine hydrobromide 300 mg qhs II (13) Gastrointestinal related, nausea and vomiting Abbreviations: DIC ⫽ disseminated intravascular coagulation; HUS-TTP ⫽ hemolytic uremic syndrome–thrombotic thrombocytopenia purpura; SER ⫽ single event reported, no statistics available. cebo, but the completion rate and compliance were not detailed in the study.25 The use of severity as an outcome measure is also questionable, as almost all other trials use the frequency of cramps as the major 694 Neurology 74 February 23, 2010 outcome measure. A small Class II study using Naftidrofuryl 300 mg BID in 14 patients showed efficacy in the reduction of cramps, but dropouts were not adequately accounted for.26 Naftidrofuryl oxalate is a drug that may enhance utilization of oxygen and glucose in peripheral vascular disease and protection of brain parenchyma during anoxia; it is not available for use in the United States. A trial (n ⫽ 27) evaluated the efficacy of vitamin E 800 U qhs vs placebo and found no effect on the mean number of cramps, number of nights with cramps, or sleep disturbance.14 A Class II study using magnesium citrate (900 mg) with a sample size of 58 calculated to detect 25% reduction in cramp frequency at a power of 80% could not conclude that there was a significant improvement in the number of cramps in patients on treatment ( p ⫽ 0.07),27 and further had a high dropout rate (64%). Another Class II study evaluating the efficacy of magnesium sulfate (dose 300 mg of Mg) with a sample size of 42 calculated to detect 25% reduction in cramp frequency at a power of 90% found that treatment was not superior to placebo for number of cramps, severity, duration, or sleep disturbance.28 A Class II, double-blind, crossover study of 13 patients studied the effects of 30 mg of diltiazem hydrochloride on the number and intensity of cramps in patients experiencing 2 or more cramps per week. The trial showed a reduction (⫺5.84 to ⫺0.16 cramps per 2-week treatment phase, p ⫽ 0.04) in the number of cramps over time in patients treated with diltiazem compared to placebo, with no effect on the intensity of cramps.29 Open-label studies. Thirty patients treated with gabapentin for 9 months showed a decrease in frequency of cramps in an open-label, unblinded study.30 Eight elderly patients refractory to quinine for treatment of cramps showed response to verapamil in a small open-label study.31 A small study (n ⫽ 24) of lidocaine injected directly into the calf was shown to be as effective as quinine in reducing cramps, but there are practical limitations of this mode of administration.32 A recent open-label study on the use of levetiracetam in 20 patients with motor neuron disease showed a reduction in the frequency and severity of muscle cramps over placebo in the 9 months of treatment compared to the 3-month run-in period.33 It is worthwhile to note that although agents such as baclofen, carbamazepine, and oxcarbazepine are frequently used in clinical practice for the management and treatment of muscle cramps, there are no clinical trials in the literature evaluating their efficacy for this indication. A few case reports and reviews commenting on the efficacy of some of these agents in the treatment of particular neuropathic conditions (such as cramp-fasciculation syndrome) have been published.34,35 Also of note, variable amounts of quinine derivatives are present in consumer products such as tonic water. Although there are a few case reports reporting their efficacy in treatment of muscle cramps, there are insufficient data to allow a specific comment on their use.36 Adverse events. No serious side effects occurred in trials evaluating gabapentin, vitamin B complex, diltiazem, and magnesium for treatment of muscle cramps. Minor side effects such as lightheadedness, nausea, and abdominal discomfort occurred infrequently and with equal frequency in controls and treatment groups in trials of vitamin B25 and magnesium.27,28 Diarrhea was equally common (10%) in magnesium- and placebo-treated patients in one trial27 and slightly more frequent in magnesiumtreated patients (30% vs 17%, p ⫽ 0.1) in another trial.28 Minor side effects that occurred more frequently with gabapentin treatment included lightheadedness, drowsiness, falls, and limb swelling24 and with Naftidrofuryl treatment included mild gastrointestinal discomfort.26 A small trial of diltiazem did not report any side effects in treated or placebo patients.29 Conclusion. On the basis of single Class II studies, Naftidrofuryl, vitamin B complex, and diltiazem are possibly effective in the treatment of muscle cramps. Naftidrofuryl is currently not available in the United States. Data regarding the use of magnesium preparations (2 Class II studies) and gabapentin (1 study in ALS) show that these agents are probably not effective in the treatment of muscle cramps. Recommendation. Naftidrofuryl, diltiazem, and vitamin B complex may be considered for the treatment of muscle cramps (Level C). RECOMMENDATIONS FOR FUTURE RESEARCH Given the lack of evidence for any con- vincing treatments for muscle cramps, further research is indicated. Further investigations into the efficacy and adverse effects of medications such as baclofen, carbamazepine, oxcarbazepine, levetiracetam, lidocaine, vitamin B complex, Naftidrofuryl, gabapentin, magnesium, and calcium channel blockers are warranted. Future studies should also include an assessment of the impact of cramps on the quality of life and nonpharmacologic interventions in the treatment of muscle cramps. DISCLOSURE Dr. Katzberg has received funding for travel from the Muscular Dystrophy Association. Dr. Khan reports no disclosures. Dr. So receives royalties from the publication of Occupational & Environmental Medicine (Appleton & Lange, 2007) and articles published in UpToDate (2007); receives research support from Pfizer Inc, NeurogesX, Inc., and the NIH (NIEHS R01 [Co-I], NIEHS R01 [Co-I], and NINDS R01 [Site PI]); estimates 10% of his clinical effort is spent on EMG; and holds equity in Satoris, Inc. DISCLAIMER This statement is provided as an educational service of the American Academy of Neurology. It is based on an assessment of current scientific and clinical information. It is not intended to include all possible proper methods of care for a particular neurologic problem or all legitimate criteria for choosing to use a specific procedure. Neither is it intended to exclude any reasonable alternative methodologies. The AAN recognizes that specific patient care decisions are the prerogative of the patient and the physician caring for the patient, based on all of the circumstances involved. CONFLICT OF INTEREST The American Academy of Neurology is committed to producing independent, critical and truthful clinical practice guidelines (CPGs). Significant efforts are made to minimize the potential for conflicts of interest to influence the recommendations of this CPG. To the extent possible, the AAN keeps separate those who have a financial stake in the success or failure of the products appraised in the CPGs and the developers of the guidelines. Conflict of interest forms were obtained from all authors and reviewed by an oversight committee prior to project initiation. AAN limits the participation of authors with substantial conflicts of interest. The AAN forbids commercial participation in, or funding of, guideline projects. Drafts of the guideline have been reviewed by at least three AAN committees, a network of neurologists, Neurology® peer reviewers and representatives from related fields. The AAN Guideline Author Conflict of Interest Policy can be viewed at www.aan.com. Received July 23, 2009. Accepted in final form November 9, 2009. REFERENCES 1. Abdulla AJ, Jones P, Pearce V. Leg cramps in the elderly: prevalence, drug and disease associations. Int J Clin Pract 1999;53:494 – 496. 2. Oboler SK, Prochazka AV, Meyer TJ. Leg symptoms in outpatient veterans. West J Med 1991;155:256 –259. 3. Layzer RB. The origin of muscle fasciculations and cramps. Muscle Nerve 1994;17:1243–1249. 4. Miller TM, Layzer RB. Muscle cramps. Muscle Nerve 2005;32:431– 442. 5. Schwellnus MP. Muscle cramping in the marathon: aetiology and risk factors. Sports Med 2007;37:364 –367. 6. Salvatore CA. Leg cramp syndrome in pregnancy. Obstet Gynecol 1961;17:634 – 639. 7. Moss HK, Herrman LG. The use of quinine for relief of “night cramps” in the extremities. JAMA 1940;115:1358 – 1359. 8. Food and Drug Administration, Department of Health and Human Services. Drug products containing quinine; enforcement action dates. Federal Register 2006;71:75557–75560. 9. Daniell HW. Simple cure for nocturnal leg cramps. N Engl J Med 1979;301:216. 10. Coppin RJ, Wicke DM, Little PS. Managing nocturnal leg cramps: calf-stretching exercises and cessation of quinine treatment: a factorial randomised controlled trial. Br J Gen Pract 2005;55:186 –191. 11. Jansen PH, Veenhuizen KC, Wesseling AI, de Boo T, Verbeek AL. Randomised controlled trial of hydroquinine in muscle cramps. Lancet 1997;349:528 –532. 12. Diener HC, Dethlefsen U, Dethlefsen-Gruber S, Verbeek P. Efficacy of quinine in treating muscle cramps: a doubleblind, placebo-controlled, parallel-group, multicentre trial. Int J Clin Pract 2002;56:243–246. Neurology 74 February 23, 2010 695 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. Jansen PH, Veenhuizen KC, Verbeek AL, Straatman H. Effectiveness of hydroquinine in preventing frequent ordinary muscle cramp outlasts actual administration. J Neurol Sci 1994;122:157–161. 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– 1880. Warburton A, Royston JF, O’Neill CJA, et al. A quinine a day keeps the leg cramps away? Br J Clin Pharmacol 1987; 23:459 – 465. Sidorov J. Quinine sulfate for leg cramps: does it work? J Am Geriatr Soc 1993;41:498 –500. Fung MC, Holbrook JH. Placebo-controlled trial of quinine therapy for nocturnal leg cramps. West J Med 1989; 151:42– 44. Lim SH. Randomised double-blind trial of quinine sulphate for nocturnal leg cramp. Br J Clin Pract 1986;40:462. Jones K, Castleden CM. A double blind comparison of quinine sulphate and placebo in muscle cramps. Age Ageing 1983;12:155–158. Dunn NR. Effectiveness of quinine for night cramps. Br J Gen Pract 1993;43:127–128. Woodfield R, Goodyear-Smith F, Arroll B. N-of-1 trials of quinine efficacy in skeletal muscle cramps of the leg. Br J Gen Pract 2005;55:181–185. Parrow A, Samuelsson SM. Use of chloroquine phosphate–a new treatment for spontaneous leg cramps. Acta Med Scand 1967;181:237–244. Bateman DN, Dyson EH. Quinine toxicity. Adv Drug React 1986;4:215–233. Miller RG, Moore DH, Gelinas DF, et al. Phase III randomized trial of gabapentin in patients with amyotrophic lateral sclerosis. Neurology 2001;56:843– 848. Chan P, Huang TY, Chen YJ, Huang WP, Liu YC. Randomized, double-blind, placebo-controlled study of the safety and efficacy of vitamin B complex in the treatment of nocturnal leg cramps in elderly patients with hypertension. J Clin Pharmacol 1998;38:1151–1154. 26. Young JB, Connolly MJ. Naftidrofuryl treatment for rest cramp. Postgrad Med J 1993;69:624 – 626. 27. Roffe C, Sills S, Crome P, Jones P. Randomised, crossover, placebo controlled trial of magnesium citrate in the treatment of chronic persistent leg cramps. Med Sci Monit 2002;8:CR326 –CR330. 28. Frusso R, Zarate M, Augustovski F, Rubinstein A. Magnesium for the treatment of nocturnal leg cramps: a crossover randomized trial. J Fam Pract 1999;48:868 – 871. 29. Voon WC, Sheu SH. Diltiazem for nocturnal leg cramps. Age Ageing 2001;30:91–92. 30. Serrao M, Rossi P, Cardinali P, Valente G, Parisi L, Pierelli F. Gabapentin treatment for muscle cramps: an open-label trial. Clin Neuropharmacol 2000;23:45– 49. 31. Baltodano N, Gallo BV, Weidler DJ. Verapamil vs quinine in recumbent nocturnal leg cramps in the elderly. Arch Intern Med 1988;148:1969 –1970. 32. Prateepavanich P, Kupniratsaikul V, Charoensak T. The relationship between myofascial trigger points of gastrocnemius muscle and nocturnal calf cramps. J Med Assoc Thai 1999;82:451– 459. 33. Bedlack RS, Pastula DM, Hawes J, Heydt D. Open-label pilot trial of levetiracetam for cramps and spasticity in patients with motor neuron disease. Amyotroph Lateral Scler 2008;26:1– 6. 34. Tahmoush AJ, Alonso RJ, Tahmoush GP, HeimanPatterson TD. Cramp-fasciculation syndrome: a treatable, hyperexcitable peripheral nerve disorder. Neurology 1991; 41:1021–1024. 35. Lagueny A. Cramp-fasciculation syndrome. Rev Neurol 2005;161:1260 –1266. 36. Brasic JR. Should people with nocturnal leg cramps drink tonic water and bitter lemon? Psychol Rep 1999;84:355– 367. Endorsed by the American Association of Neuromuscular & Electrodiagnostic Medicine. 696 Neurology 74 February 23, 2010 AAN Summary of Evidence-based Guideline for PATIENTS and their FAMILIES DRUG TREATMENTS FOR SYMPTOMS OF MUSCLE CRAMPS This fact sheet may help you understand which drugs are the best choices for treating symptoms of muscle cramps. Neurologists from the American Academy of Neurology are doctors who identify and treat diseases of the brain and nervous system. The following evidence-based information* is provided by experts who carefully reviewed all available scientific studies on drugs for treating muscle cramps. There are several drugs available to treat symptoms of muscle cramps. However, more research is needed on their safety and effectiveness. If you have muscle cramps, it is important to see your doctor to find out the cause. Muscle cramps due to menstruation (monthly periods) or to kidney or muscle diseases are not discussed here. What is a muscle cramp? A muscle cramp is a contraction (tightening) of the muscle. This contraction often is painful and can be caused by movement. The contraction also is involuntary. This means the muscle tightens without the person’s control. The cramping causes the muscle to feel hard. The muscle often seems to be bulging. The cramps can affect one muscle or a group of muscles. Muscle cramps differ from muscle twitches. Twitches are slight movements in a small area of a muscle. Many people experience muscle cramps. For some, the cramps happen often and are very severe. For these people, muscle cramps can be disabling. Muscle cramps have many causes. The main causes are dehydration (not enough fluid in the body), heavy exercise, or muscle fatigue or tiredness. Other causes include alcoholism, drug use, pregnancy, or poor nutrition. However, the cause is not always known. In some cases, muscle cramps are a sign of a more serious problem. Talk with your doctor to find out more about possible causes. What drugs help treat muscle cramps? There are several drugs available to treat symptoms of muscle cramps. There is weak evidence that naftidrofuryl, diltiazem, and vitamin B complex may help treat these symptoms. However, as of February 2010, naftidrofuryl is not available in the United States. There are no serious side effects of these drugs. Studies reported some mild side effects, such as lightheadedness, nausea (upset stomach), and diarrhea. Mild indigestion from naftidrofuryl use also has been reported. Research shows magnesium supplements and gabapentin likely are not helpful treatments. Strong evidence shows that the quinine drug family helps to treat symptoms of muscle cramps. However, quinine poses a risk of serious side effects. These include blood and kidney problems. These risks are serious but uncommon. Milder risks include headache, sweating, blurred vision, and ringing of the ears. In December 2006, the US Food and Drug Administration (FDA) issued a news release on risks of quinine use. The release warns against using quinine for leg cramps. The release also reports that 93 deaths since 1969 occurred from quinine use. To learn more, go to www.fda.gov/NewsEvents/ Newsroom/PressAnnouncements/2006/ucm108799.htm. Due to these risks, quinine generally should be avoided. Doctors should prescribe this drug only in special cases. Quinine should be considered only when cramp symptoms are very disabling and other drugs have not helped. Also, people considering quinine should be informed of possible risks. Anyone taking quinine should be monitored for serious side effects. More research is needed on the safety and effectiveness of all these drug treatments. Such studies also should focus on how muscle cramps affect a person’s quality of life. Are there therapies that help with muscle cramps? Some health experts recommend stretching muscles to relieve cramping. However, there is not enough evidence to show if therapies such as stretching are helpful. Future studies of muscle cramps should look at how useful such therapies are. This statement is provided as an educational service of the American Academy of Neurology. It is based on an assessment of current scientific and clinical information. It is not intended to include all possible proper methods of care for a particular neurologic problem or all legitimate criteria for choosing to use a specific procedure. Neither is it intended to exclude any reasonable alternative methodologies. The AAN recognizes that specific patient care decisions are the prerogative of the patient and the physician caring for the patient, based on all of the circumstances involved. *After the experts review all of the published research studies, they describe the strength of the evidence supporting each recommendation: Strong evidence = more than one high-quality scientific study Good evidence = at least one high-quality scientific study or two or more studies of a lesser quality Weak evidence = the studies, while supportive, are weak in design or strength of the findings Not enough evidence = either different studies have come to conflicting results or there are no studies of reasonable quality ©2010 American Academy of Neurology Copies of this summary and additional companion tools are available at www.aan.com or through AAN Member Services at (800) 879-1960. 1080 Montreal Avenue • St. Paul, MN 55116 www.aan.com • (651) 695-1940 AAN Summary of Evidence-based Guideline for CLINICIANS Symptomatic Treatment for Muscle Cramps This is a summary of the American Academy of Neurology (AAN) guideline (Neurology ® 2010; 74:691–696) regarding symptomatic treatment for muscle cramps. Please refer to the full guideline at www.aan.com for more information. NONPHARMACOLOGIC TREATMENTS Are there effective nonpharmacologic treatments for muscle cramps? Insufficient evidence Data are insufficient to support or refute the efficacy of calf stretching in reducing the frequency of muscle cramps (Level U†). PHARMACOLOGIC TREATMENTS Is quinine effective in the treatment of muscle cramps? Strong evidence Although likely effective (Level A), the use of quinine derivatives for treatment of cramps should be avoided for routine treatment of cramps. These agents should only be considered when cramps are very disabling, no other agents relieve symptoms, and there is careful monitoring of side effects. They should only be used after informing the patient of the potentially serious side effects. Are there any other pharmacologic treatments effective for the treatment of muscle cramps? Weak evidence Naftidrofuryl, diltiazem, and vitamin B complex may be considered for the treatment of muscle cramps (Level C). Classification of Recommendations: A = Established as effective, ineffective or harmful (or established as useful/predictive or not useful/predictive) for the given condition in the specified population. (Level A rating requires at least two consistent Class I studies.)* B = Probably effective, ineffective or harmful (or probably useful/predictive or not useful/predictive) for the given condition in the specified population. (Level B rating requires at least one Class I study or two consistent Class II studies.) C = Possibly effective, ineffective or harmful (or possibly useful/ predictive or not useful/predictive) for the given condition in the specified population. (Level C rating requires at least one Class II study or two consistent Class III studies.) U = Data inadequate or conflicting; given current knowledge, treatment (test, predictor) is unproven. † *In exceptional cases, one convincing Class I study may suffice for an “A” recommendation if 1) all criteria are met, 2) the magnitude of effect is large (relative rate improved outcome >5 and the lower limit of the confidence interval is >2). Classification of Evidence for Studies of Therapeutic Intervention: Class I = A randomized, controlled clinical trial of the intervention of interest with masked or objective outcome assessment, in a representative population. Relevant baseline characteristics are presented and substantially equivalent among treatment groups or there is appropriate statistical adjustment for differences. The following are also required: a. concealed allocation, b. primary outcome(s) clearly defined, c. exclusion/inclusion criteria clearly defined, d. adequate accounting for dropouts (with at least 80% of enrolled subjects completing the study) and crossovers with numbers sufficiently low to have minimal potential for bias, e. for noninferiority or equivalence trials claiming to prove efficacy for one or both drugs, the following are also required**: 1. The authors explicitly state the clinically meaningful difference to be excluded by defining the threshold for equivalence or noninferiority. 2. The standard treatment used in the study is substantially similar to that used in previous studies establishing efficacy of the standard treatment (e.g., for a drug, the mode of administration, dose and dosage adjustments are similar to those previously shown to be effective). 3. The inclusion and exclusion criteria for patient selection and the outcomes of patients on the standard treatment are comparable to those of previous studies establishing efficacy of the standard treatment. 4. The interpretation of the results of the study is based upon a per protocol analysis that takes into account dropouts or crossovers. Class II = A randomized controlled clinical trial of the intervention of interest in a representative population with masked or objective outcome assessment that lacks one criteria a–e above or a prospective matched cohort study with masked or objective outcome assessment in a representative population that meets b–e above. Relevant baseline characteristics are presented and substantially equivalent among treatment groups or there is appropriate statistical adjustment for differences. Class III = All other controlled trials (including well-defined natural history controls or patients serving as own controls) in a representative population, where outcome is independently assessed, or independently derived by objective outcome measurement.*** Class IV = Studies not meeting Class I, II or III criteria including consensus or expert opinion. **Note that numbers 1–3 in Class Ie are required for Class II in equivalence trials. If any one of the three is missing, the class is automatically downgraded to Class III. ***Objective outcome measurement: an outcome measure that is unlikely to be affected by an observer’s (patient, treating physician, investigator) expectation or bias (e.g., blood tests, administrative outcome data). This is an educational service of the American Academy of Neurology. It is designed to provide members with evidence-based guideline recommendations to assist the decision making in patient care. It is based on an assessment of current scientific and clinical information and is not intended to exclude any reasonable alternative methodologies. The AAN recognizes that specific patient care decisions are the prerogative of the patient and the physician caring for the patient, and are based on the circumstances involved. Physicians are encouraged to carefully review the full AAN guidelines so they understand all recommendations associated with care of these patients. ©2010 American Academy of Neurology Copies of this summary and additional companion tools are available at www.aan.com or through AAN Member Services at (800) 879-1960. 1080 Montreal Avenue • St. Paul, MN 55116 www.aan.com • (651) 695-1940 Hans Dieter Katzberg Discusses New Guideline on Symptomatic Treatment for Muscle Cramps The AAN has published a new guideline on symptomatic treatment for muscle cramps. The guideline recommends that the drug quinine, although effective, be avoided for treatment of routine muscle cramps due to uncommon but serious side effects. Lead guideline author Hans D. Katzberg, MD, spoke with Neil A. Busis, MD, FAAN, AAN.com Practice & Technology Website Associate Editor. AAN.com: Please tell us about the 2006 Food and Drug Administration advisory that warned against the off-label use of quinine sulfate and its derivatives in the treatment of muscle cramps. Katzberg: In December 2006, the FDA issued a statement ordering unapproved quinine drugs to be pulled off the market and warning consumers against the use of these drugs for the treatment of muscle cramps. The reason for the statement was 663 reports of serious adverse events (the main ones being hematologic events such as idiopathic thrombocytopenic purpura (ITP), or thrombotic thrombocytopenic purpura (TTP)), as well as 93 deaths attributed to quinine drugs reported since 1969. The FDA stated that these harms outweighed any potential benefit from the medication for use in treatment of muscle cramps. This statement has now made it onto a boxed warning for quinine sulfate, which is still manufactured in limited amounts and indicated only for the treatment of plasmodium falciparum malaria in the United States. AAN.com: What is the purpose of this AAN clinical practice guideline? Katzberg: To educate physicians and the public on the role of quinine for treatment of muscle cramp symptoms and to increase knowledge of alternative symptomatic treatments for muscle cramps. By highlighting the lack of available evidence, we also hope to encourage research on alternative treatments for muscle cramps. AAN.com: Who is the target audience? Katzberg: Health care providers who treat patients with muscle cramps as well as patients with muscle cramps and their families and caregivers. AAN.com: What are the main conclusions of these new guidelines? Katzberg: First, there are several drugs available to treat muscle cramp symptoms, but more research is needed on their safety and effectiveness. Also, we found evidence that quinine drugs effectively treat muscle cramp symptoms, but should be generally avoided due to uncommon but serious side effects. 1080 Montreal Avenue • St. Paul, Minnesota 55116 • tel: 651.695.1940 • fax: 651.695.2791 • www.aan.com AAN.com: How should these guidelines be used in clinical practice? Katzberg: Physicians should be aware that disabling muscle cramps may be due to a number of medical or neurologic conditions, which should be ruled out before diagnosing someone with idiopathic cramps. When symptomatic treatment is required, a number of drugs included in our review may be used, including calcium channel blockers and vitamin B complex. Quinine drugs should be considered only in special cases: when cramp symptoms are very disabling, when other drugs don't help, and when side effects are carefully watched. AAN.com: Class I studies showed the efficacy of quinine derivatives for treatment of muscle cramps. However, their benefit was modest. Please explain. Katzberg: In the two Class I studies identified, there was a reduction of approximately 25 to 40 percent in number of muscle cramps, which translated into a reduction of two to five cramps per three-week treatment phase: this is significant, but it does not eliminate or even nearly eliminate muscle cramps. AAN.com: There were significant adverse effects from quinine derivatives in published prospective trials as well as case reports. What were they? Katzberg: The significant major side effects from quinine drugs were hematological abnormalities such as hemolytic uremic syndrome-thrombotic thrombocytopenia purpura (HUS-TTP), disseminated intravascular coagulation (DIC), and bleeding diathesis. Less common side effects included hypoglycemia, retinal toxicity, hepatotoxicity, cardiac arrhythmias, pulmonary edema, and hypersensitivity reactions. AAN.com: The guidelines recommended against routine use of quinine derivatives for the management of cramps, but in select patients it can be considered for an individual therapeutic trial. How do you recommend clinicians work through this decision process? Katzberg: We recommend that clinicians use any of the alternate medications listed in the practice parameter that have some evidence for efficacy in the management of muscle cramps. If a patient is experiencing significant disability from cramps and is still refractory to these treatments, a trial of quinine drugs may be warranted if the patient is aware of all the potential side effects, including death, associated with their use. AAN.com: What are the roles of vitamin B complex, naftidrofuryl, and calcium channel blockers such as diltiazem in the management of cramps? Katzberg: Diltiazem and vitamin B complex each have Level C evidence and are acceptable medications as first and second line treatment of symptomatic muscle cramps. Naftidrofuryl also has Level C evidence for treatment of muscle cramps; however, it is not available for use in the United States. 1080 Montreal Avenue • St. Paul, Minnesota 55116 • tel: 651.695.1940 • fax: 651.695.2791 • www.aan.com Author Disclosure Within the past 24 months, Dr. Busis received personal compensation for his work as AAN.com Practice and Technology Editor, as well as for speaking at AAN and AANEM courses. In the same period, he served as Editorial Advisor for Neurology Coding Alert. He has also given expert testimony on coding issues. 1080 Montreal Avenue • St. Paul, Minnesota 55116 • tel: 651.695.1940 • fax: 651.695.2791 • www.aan.com