今日の臨床サポート

こむらがえり・下肢つり・有痛性の筋収縮

著者: 石井一弘 筑波⼤学 医学医療系 神経内科学

監修: 庄司進一 筑波大学

著者校正/監修レビュー済:2022/04/27
患者向け説明資料

概要・推奨   

  1. 筋けいれんを起こし得る基礎疾患の治療をまず第一に考える。次に薬剤性が疑われるのであれば、疑わしい薬剤を中止して筋けいれんの症状が軽減することを確認する(推奨度1、M~2、R)
薬剤監修について:
オーダー内の薬剤用量は日本医科大学付属病院 薬剤部 部長 伊勢雄也 以下、林太祐、渡邉裕次、井ノ口岳洋、梅田将光による疑義照会のプロセスを実施、疑義照会の対象については著者の方による再確認を実施しております。
※薬剤中分類、用法、同効薬、診療報酬は、エルゼビアが独自に作成した薬剤情報であり、
著者により作成された情報ではありません。
尚、用法は添付文書より、同効薬は、薬剤師監修のもとで作成しております。
※薬剤情報の(適外/適内/⽤量内/⽤量外/㊜)等の表記は、エルゼビアジャパン編集部によって記載日時にレセプトチェックソフトなどで確認し作成しております。ただし、これらの記載は、実際の保険適用の査定において保険適用及び保険適用外と判断されることを保証するものではありません。また、検査薬、輸液、血液製剤、全身麻酔薬、抗癌剤等の薬剤は保険適用の記載の一部を割愛させていただいています。
(詳細はこちらを参照)
著者のCOI(Conflicts of Interest)開示:
石井一弘 : 奨学(奨励)寄付など(エーザイ株式会社)[2022年]
監修:庄司進一 : 特に申告事項無し[2022年]

改訂のポイント:
  1. 定期レビューを行い、① 肝硬変患者への経口タウリン投与でのRCT結果、② 薬剤性筋けいれんにおける原因薬物の追記、③ 治療薬の追記を行った。

病態・疫学・診察

疫学情報・病態・注意事項  
  1. 有痛性の筋収縮状態は、下腿三頭筋に最も多くみられ、これを”こむらがえり”という。または「筋(すじ)がつる」という。英訳はleg cramp, muscle cramp(腓腹筋の筋けいれん)[1]。病態機序は必ずしも明らかでなく、伴う疼痛の原因も明確でない。
  1. 生理的なこむらがえりは健常人の90%以上が経験している。最も頻繁に認められる生理的なこむらがえりは夜間睡眠時腓腹筋に非対称性に生ずる激烈な痛みを伴う筋の異常収縮である。腓腹筋に限らず、全身いたるところで起き得る。健常人でも、水泳中など筋過労時運動中にも起きる。腓腹筋に起きる場合、筋肉の最も短縮したときに起き、随意的に短縮させて誘発することもできる。発作は数十秒から数分でおさまるが、疼痛が残ることが多い。攣縮している筋肉を伸展させて発作を止めることができる。他に症状が無ければ生理的なこむらがえりと評価する。
  1. こむらがえりの頻度として、高齢者の大規模研究では50%以上が夜間筋けいれんを経験している[2]。男女差はない。筋けいれんの発生頻度は年齢とともに増加し、高齢者を苦しめる疾患の1つである[3]。 家庭医に登録している233人の住民を対象にした調査では、安静時にこむらがえりのある人は37%で、高齢者により多かった。83%が下腿筋に自覚していた。夜間に多く、平均9分持続していた。頻度は少ない人が多かったが、1週に3回以上が40%、1日に1回以上の人は6%いた。86人のうち32%が家庭医に報告していた[3]。 英国の病院の老年科外来で65歳以上を対象にした調査では、365人中50%にこむらがえりがあった。夜間に多く(62%)、期間は10年以上が20%、最近半年以内が9%であった [4][5]
  1. 妊娠に関連して、33~50%の妊婦は筋けいれんを経験しており、週数が進むに連れて、症状が増悪する傾向にある[6]
  1. 子供に起こる筋けいれんは7.3%にみられ、成人の筋けいれんと臨床所見が異なる。約2分間持続する筋けいれんを年に1~数回経験する程度である[7]
問診・診察のポイント  
  1. 有痛性筋けいれんの生じる筋:局所性か全身性か? 左右対称か? 持続時間は? 安静時か運動時か? 家族歴はあるか? 色の濃い尿(ミオグロビン尿)は出るか?

これより先の閲覧には個人契約のトライアルまたはお申込みが必要です。

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文献 

S K Oboler, A V Prochazka, T J Meyer
Leg symptoms in outpatient veterans.
West J Med. 1991 Sep;155(3):256-9.
Abstract/Text In a survey of outpatients at the Denver Veterans Affairs Medical Center for common leg symptoms--515 questionnaires returned in a 3-week period--56% reported nocturnal leg cramps, 29% reported the restless leg syndrome, and 49% reported symptoms of peripheral neuropathy. Only 33% of patients had no symptoms relating to their legs. Patients often did not report these symptoms to their physician but were more likely to do so if the symptoms were frequent. Conditions especially related to leg symptoms were hypertension, peripheral vascular disease, coronary artery disease, cerebrovascular disease, kidney disease, and hypokalemia. Most patients did not receive effective therapy for these symptoms.

PMID 1659038
J R Naylor, J B Young
A general population survey of rest cramps.
Age Ageing. 1994 Sep;23(5):418-20.
Abstract/Text Two hundred and eighteen subjects, out of 250 individuals taken from a general practice register, returned completed questionnaires giving details about rest cramps, and a further 15 were contacted by telephone. The overall prevalence of rest cramps in the survey population was 37%. The symptom was more prevalent in older subjects. Rest cramps were most commonly experienced in the muscles of the leg, in 83% of the 86 cramp sufferers. Symptoms were usually present at night (73%). On average cramp episodes lasted for 9 min (95%CI 6.7-11.2). Most cramps sufferers experienced symptoms infrequently, but 40% had cramp episodes more than three times per week and 6% complained of at least one episode per day or night. Twenty-one per cent of cramp sufferers described their symptoms as very distressing. A minority, 32% of the 86 cramp sufferers, had reported the symptoms to a general practitioner although the 86 subjects self-rated their health more negatively than the individuals without muscle cramps. There was a significant, positive association between rest cramps and symptoms of angina or intermittent claudication although these two factors only accounted for 12% of the variance, suggesting that peripheral vascular disease may play a relevant but limited role in the aetiology of rest cramps.

PMID 7825490
A J Abdulla, P W Jones, V R Pearce
Leg cramps in the elderly: prevalence, drug and disease associations.
Int J Clin Pract. 1999 Oct-Nov;53(7):494-6.
Abstract/Text To determine the prevalence of leg cramps in elderly outpatients and their association any underlying diseases and concomitant drug intake, we conducted a cross-sectional study using an in-depth questionnaire. A total of 365 patients aged 65 years and over (mean 78.5 years) attending our outpatient clinic participated in the study. The prevalence of leg cramps was 50%. Cramps were commoner in females (56%) than in males (40%). Although reported to occur anytime throughout the 24 hours, cramps were most prevalent at night (62%). In many patients, leg cramps were a long-standing complaint: 20% had been suffering with them for more than 10 years, whereas only 9% of patients reported them first starting within the last six months. Only 73 (40%) sufferers had informed their practitioner; of these, 39 (53%) received treatment, of whom 26 gained benefit. Leg cramps were strongly associated with peripheral vascular disease (odds ratio 2.9, 95% CI 1.89-4.55, p < 0.00001), arthritis (odds ratio 2.26, 95% CI 1.48-3.45, p = 0.0001) and female gender (odds ratio 1.96, 95% CI 1.28-3.03, p = 0.002). Heart failure, hypertension, diabetes mellitus and stroke were not significantly associated. Except for a causal association with analgesic use, no positive association could be shown with any other class of drugs, including diuretics.

PMID 10692732
Jennifer G Hensley
Leg cramps and restless legs syndrome during pregnancy.
J Midwifery Womens Health. 2009 May-Jun;54(3):211-8. doi: 10.1016/j.jmwh.2009.01.003.
Abstract/Text Sleep disturbance during pregnancy can result in excessive daytime sleepiness, diminished daytime performance, inability to concentrate, irritability, and the potential for an increased length of labor and increased risk of operative birth. Sleep disturbance may be the result of a sleep disorder, such as leg cramps, a common yet benign disorder, or restless legs syndrome, a sensorimotor disorder. Both disrupt sleep, are distressing to the pregnant woman, and mimic one another and other serious disorders. During pregnancy, up to 30% of women can be affected by leg cramps, and up to 26% can be affected by restless legs syndrome.

PMID 19410213
A K Leung, B E Wong, P Y Chan, H Y Cho
Nocturnal leg cramps in children: incidence and clinical characteristics.
J Natl Med Assoc. 1999 Jun;91(6):329-32.
Abstract/Text The records of 2527 healthy children seen in an ambulatory care clinic were evaluated for nocturnal leg cramps in the preceding 12 months, frequency and duration of the cramps, whether the cramps affected one leg or both legs at a time, whether there was associated muscle cramps in feet, whether the cramps occurred when the child was awake or asleep, and whether there was residual tenderness in the affected muscles. Nocturnal leg cramps were present in 185 children for an overall incidence of 7.3%. Leg cramps were noted only in children aged > or = 8 years. The incidence increased at 12 years and peaked at 16 to 18 years of age. A majority (81.6%) of the affected children had nocturnal leg cramps 1 to 4 times per year. The mean duration of episodes was 1.7 minutes. Leg cramps were unilateral in 98.9% of cases and the ipsilateral foot also was involved in 18.9% of cases. One hundred thirty-five (73%) children had leg cramps while asleep, and the remaining 23 (12.4%) children had leg cramps in either state. Fifty-seven (30.8%) children had residual tenderness in the affected muscles. The mean duration of residual tenderness was 33.2 minutes (range: 2 minutes-1 day). We conclude that nocturnal leg cramps are common in children aged > 12 years. A majority of the affected children have leg cramps 1 to 4 times per year. The cramps are usually unilateral and occur when the children are asleep. Normal duration of the leg cramp is < 2 minutes. Residual tenderness is present in approximately 30% of the affected children. Residual tenderness, if present, usually lasts for half an hour.

PMID 10388258
Abstract/Text OBJECTIVE: To assess quantitatively the efficacy of quinine (as quinine sulphate) compared with placebo in the treatment of nocturnal leg cramps.
DESIGN: A meta-analysis of six randomised, double blind, crossover trials.
SETTING: Randomised trials that were available as of April 1994.
SUBJECTS: A total of 107 general ambulatory patients who suffered from regular nocturnal leg cramps from six clinical trials.
RESULTS: Data from individual patients were used to calculate point estimates and 95% confidence intervals for each of the outcome measures reported by these studies. Treatment with quinine resulted in a significant reduction in the number of cramps for a four week period compared with placebo (8.83 fewer cramps; 95% confidence interval 4.16 to 13.49). Treatment with quinine reduced the number of nights with cramps by 27.4% (24.0% to 30.8%) compared with placebo. Treatment did not produce a significant change in the severity or duration of individual nocturnal leg cramps. Side effects were uncommon.
CONCLUSIONS: The results indicate that quinine can prevent nocturnal leg cramps in general ambulatory populations. Given the possible serious side effects of treatment with quinine, the benefits and risks in patients taking this drug should be closely monitored.

PMID 7827545
M Man-Son-Hing, G Wells, A Lau
Quinine for nocturnal leg cramps: a meta-analysis including unpublished data.
J Gen Intern Med. 1998 Sep;13(9):600-6.
Abstract/Text OBJECTIVE: With respect to the use of quinine for the treatment of nocturnal leg cramps, to determine whether the findings of a previously performed meta-analysis of published data are altered with the addition of unpublished data, and whether publication bias is present in this area.
DESIGN: A meta-analysis of eight (four published and four unpublished) randomized, double-blind, placebo-controlled trials, seven of which had a crossover design.
SETTING: Randomized trials that were available as of July 1997.
SUBJECTS: Ambulatory patients (659) who suffered from regular nocturnal leg cramps.
MAIN RESULTS: When individual patient data from all crossover studies were pooled, persons had 3.60 (95% confidence interval [CI] 2.15, 5.05) fewer cramps in a 4-week period when taking quinine compared with placebo. This compared with an estimate of 8.83 fewer cramps (95% CI 4.16, 13.49) from pooling published studies alone. The corresponding relative risk reductions were 21% (95% CI 12%, 30%) and 43% (95% CI 21%, 65%), respectively. Compared with placebo, the use of quinine was associated with an increased incidence of side effects, particularly tinnitus. Publication bias is present in the reporting of the efficacy of quinine for this indication, as almost all published studies reported larger estimates of its efficacy than did unpublished studies.
CONCLUSIONS: This study confirms that quinine is efficacious in the prevention of nocturnal leg cramps. However, its benefit may not be as large as reported from the pooling of published studies alone. Given the side effect profile of quinine, nonpharmacologic therapy (e.g., regular passive stretching of the affected muscle) is the best first-line treatment. For persons who find this ineffective and whose quality of life is significantly affected, a trial of quinine is warranted. Prescribing physicians must closely monitor the risks and benefits in individual patients. Publication bias is present in this area even though there is controversy about the role of quinine in the treatment of leg cramps. To minimize the possibility of this bias, persons performing medication-related meta-analyses should seek high-quality unpublished data from drug regulatory agencies and pharmaceutical companies.

PMID 9754515
H W Daniell
Simple cure for nocturnal leg cramps.
N Engl J Med. 1979 Jul 26;301(4):216.
Abstract/Text
PMID 449985
Richard J Coppin, Dorothy M Wicke, Paul S Little
Managing nocturnal leg cramps--calf-stretching exercises and cessation of quinine treatment: a factorial randomised controlled trial.
Br J Gen Pract. 2005 Mar;55(512):186-91.
Abstract/Text BACKGROUND: Quinine is a common treatment for nocturnal leg cramps but has potential side effects. An uncontrolled study suggested that calf-stretching exercises could prevent nocturnal leg cramps (night cramps) but these findings have never been confirmed.
AIM: To assess the effect of calf-stretching exercises and cessation of quinine treatment for patients with night cramps taking quinine.
DESIGN OF STUDY: Randomised controlled trial.
SETTING: Twenty-eight general practices in southern England.
METHOD: One hundred and ninety-one patients prescribed quinine for night cramps were randomised to one of four groups defined by two "advice" factors: undertake exercises and stop quinine. After 6 weeks they were advised that they could take quinine and undertake the exercises freely. Documentation of cramp at 12 weeks was achieved in 181 (95%) patients. Main outcome measures were: symptom burden score, and frequency of night cramps and quinine usage.
RESULTS: At 12 weeks there was no significant difference in number of cramps in the previous 4 weeks (exercise = 1.95, 95% confidence interval [CI] = -3.01 to 6.90; quinine cessation = 3.45, 95% CI = -1.52 to 8.41) nor symptom burden or severity of cramps. However, after 12 weeks 26.5% (95% CI = 13.3% to 39.7%) more patients who had been advised to stop quinine treatment reported taking no quinine tablets in the previous week (odds ratio [OR] = 3.32, 95% CI = 1.37 to 8.06), whereas advice to do stretching exercises had no effect (OR = 0.73, 95% CI = 0.27 to 1.98).
CONCLUSIONS: Calf-stretching exercises are not effective in reducing the frequency or severity of night cramps. Advising those on long-term repeat prescriptions to try stopping quinine temporarily will result in no major problems for patients, and allow a significant number to stop medication.

PMID 15808033
Renee S Monderer, Winfred P Wu, Michael J Thorpy
Nocturnal leg cramps.
Curr Neurol Neurosci Rep. 2010 Jan;10(1):53-9. doi: 10.1007/s11910-009-0079-5.
Abstract/Text Nocturnal leg cramps are a frequent cause of sleep disturbance among the general population, especially among the elderly. These painful episodes can delay sleep onset and awaken the patient from sleep, as well as delay subsequent return to sleep. Different mechanisms have been proposed to explain this phenomenon. Although most cases of leg cramps are idiopathic, multiple secondary causes of sleep-related leg cramps have been identified as well. In this article, we review the epidemiology, pathophysiology, and risk factors and discuss the salient features of the diagnosis and workup. Finally, we review the wide array of behavioral and pharmacologic treatments that have been studied for nocturnal leg cramps.

PMID 20425227
Abstract/Text 164 patients (m = 45, w = 119; age 55.7 +/- 14.7 years) took part in a multicentric controlled parallel-double blind study in which efficacy and tolerability of the combination quinine sulfate (CAS 6119-70-6) plus theophylline ethylene diamine (CTED, CAS 317-34-0) (Limptar) in the treatment of the recurrent nocturnal leg cramps were investigated. Only patients who suffered before the begin of the study in at least three nights per week from leg cramps were included. The duration of the study was three weeks. In the first week all patients were treated in a single blind design with placebo. The subsequent 2 weeks were carried out double-blind. The global efficacy judged by the physicians and investigated for the 126 patients who took the compounds at least four days within the random phase was remarkably better for the combination than for quinine or placebo (very good and good in 87.1 vs. 63.7 vs. 39.5% of the cases; p less than 0.001; x-test). In 117 patients an analysis of the time course of the efficacy could be done from the notes in the diary (minimum duration of treatment 11 d). Already within the first week there was a highly significant decrease of nights with leg cramps within the CTED group (n = 34) from 4.68 (95% confidential interval 2.26-7.0) to 2.25 (0-6.78) in comparison to placebo (n = 40; from 4.32 [1.9-7.0] to 3.69 [1.22-6.91]) and quinine (n = 43; from 4.78 [2.22-7.0] to 3.27 [0-7.0]; F-test; p = 0.0001 resp. 0.0012).(ABSTRACT TRUNCATED AT 250 WORDS)

PMID 2043179
Sherif El-Tawil, Tarique Al Musa, Haseeb Valli, Michael P T Lunn, Ruth Brassington, Tariq El-Tawil, Markus Weber
Quinine for muscle cramps.
Cochrane Database Syst Rev. 2015 Apr 5;(4):CD005044. doi: 10.1002/14651858.CD005044.pub3. Epub 2015 Apr 5.
Abstract/Text BACKGROUND: Muscle cramps can occur anywhere and for many reasons. Quinine has been used to treat cramps of all causes. However, controversy continues about its efficacy and safety. This review was first published in 2010 and searches were updated in 2014.
OBJECTIVES: To assess the efficacy and safety of quinine-based agents in treating muscle cramps.
SEARCH METHODS: On 27 October 2014 we searched the Cochrane Neuromuscular Disease Group Specialized Register, CENTRAL, MEDLINE and EMBASE. We searched reference lists of articles up to 2014. We also searched for ongoing trials in November 2014.
SELECTION CRITERIA: Randomised controlled trials of people of all ages with muscle cramps in any location and of any cause, treated with quinine or its derivatives.
DATA COLLECTION AND ANALYSIS: Three review authors independently selected trials for inclusion, assessed risk of bias and extracted data. We contacted study authors for additional information. For comparisons including more than one trial, we assessed the quality of the evidence using Grading of Recommendations Assessment, Development and Evaluation (GRADE).
MAIN RESULTS: We identified 23 trials with a total of 1586 participants. Fifty-eight per cent of these participants were from five unpublished studies. Quinine was compared to placebo (20 trials, n = 1140), vitamin E (four trials, n = 543), a quinine-vitamin E combination (three trials, n = 510), a quinine-theophylline combination (one trial, n = 77), and xylocaine injections into the gastrocnemius muscle (one trial, n = 24). The most commonly used quinine dosage was 300 mg/day (range 200 to 500 mg). We found no new trials for inclusion when searches were updated in 2014.The risk of bias in the trials varied considerably. All 23 trials claimed to be randomised, but only a minority described randomisation and allocation concealment adequately.Compared to placebo, quinine significantly reduced cramp number over two weeks by 28%, cramp intensity by 10%, and cramp days by 20%. Cramp duration was not significantly affected.A significantly greater number of people suffered minor adverse events on quinine than placebo (risk difference (RD) 3%, 95% confidence interval (CI) 0% to 6%), mainly gastrointestinal symptoms. Overdoses of quinine have been reported elsewhere to cause potentially fatal adverse effects, but in the included trials there was no significant difference in major adverse events compared with placebo (RD 0%, 95% CI -1% to 2%). One participant suffered from thrombocytopenia (0.12% risk) on quinine.A quinine-vitamin E combination, vitamin E alone, and xylocaine injections into gastrocnemius were not significantly different to quinine across all outcomes, including adverse effects. Based on a single trial comparison, quinine alone was significantly less effective than a quinine-theophylline combination but with no significant differences in adverse events.
AUTHORS' CONCLUSIONS: There is low quality evidence that quinine (200 mg to 500 mg daily) significantly reduces cramp number and cramp days and moderate quality evidence that quinine reduces cramp intensity. There is moderate quality evidence that with use up to 60 days, the incidence of serious adverse events is not significantly greater than for placebo in the identified trials, but because serious adverse events can be rarely fatal, in some countries prescription of quinine is severely restricted.Evidence from single trials suggests that theophylline combined with quinine improves cramps more than quinine alone, and the effects of xylocaine injections into gastrocnemius are not significantly different to quinine across all outcomes. Low or moderate quality evidence shows no significant difference between quinine and vitamin E or quinine and quinine-vitamin E mixture. Further research into these alternatives, as well other pharmacological and non-pharmacological treatments, is thus warranted.There is no evidence to judge optimal dosage or duration of quinine treatment. Further studies using different dosages and measurement of serum quinine levels will allow a therapeutic range to be defined for muscle cramp. Because serious adverse events are not common, large population studies are required to more accurately inform incidence. Longer lengths of follow-up in future trials will help determine the duration of action following cessation of quinine as well as long-term adverse events. The search for new therapies, pharmacological and nonpharmacological, should continue and further trials should compare vitamin E, quinine-vitamin E combination, and quinine-theophylline mixture with quinine.

PMID 25842375
Abstract/Text Nocturnal leg cramps is a common and troublesome problem in elderly individuals, and their etiology is unknown. Treatment with quinine is a common practice, but the effectiveness of the drug is doubtful and adverse drug effects are common. This randomized, double-blind, placebo-controlled study was conducted to evaluate the safety and efficacy of vitamin B complex capsules (fursulthiamine 50 mg, hydroxocobalamin 250 micrograms, pyridoxal phosphate 30 mg, and riboflavin 5 mg) in 28 elderly patients with hypertension who had severe nocturnal leg cramps that disturbed their sleep. Self-reported ratings of leg cramp frequency, duration, and intensity were used to evaluate severity of nocturnal leg cramps. Both the patients taking vitamin B capsules (n = 14) and those taking placebo (n = 14) received medications three times daily, and were examined regularly at 2-week intervals for 3 months. After 3 months, 86% of the patients taking vitamin B had prominent remission of leg cramps, whereas those taking placebo had no significant difference from baseline. Treatment with vitamin B complex significantly reduced the frequency, intensity, and duration of nocturnal leg cramps. Because quinine is not without potential for side effects, and vitamin B complex is a relatively safe and effective alternative, clinicians should reconsider the treatment of choice for nocturnal leg cramps.

PMID 11301568
Natasha Chandok, Patrick Tan, Julia Uhanova, Neil Shankar, Paul Marotta
A pilot study of vitamin E for the treatment of cirrhotic muscle cramps.
Liver Int. 2011 Apr;31(4):586-7. doi: 10.1111/j.1478-3231.2011.02464.x. Epub 2011 Feb 1.
Abstract/Text
PMID 21382169
A O Roca, D Jarjoura, D Blend, A Cugino, G W Rutecki, P S Nuchikat, F C Whittier
Dialysis leg cramps. Efficacy of quinine versus vitamin E.
ASAIO J. 1992 Jul-Sep;38(3):M481-5.
Abstract/Text A controlled randomized double-blind study was done to determine the frequency and severity of leg cramps in 40 patients on dialysis with a history of leg cramps. All patients entered a 2 month placebo washout and were randomized into a 2 month double-dummy phase of quinine 325 mg at bedtime versus vitamin E 400 IU at bedtime. Of the 29 patients completing the study, 16 received quinine and 13 vitamin E. During placebo washout, the vitamin E group had a mean of 10.4 leg cramps per month, and the quinine group had a mean of 10.9. The vitamin E and quinine groups had a 1 month reduction in leg cramps to 3.3 and 3.6, respectively (p < 0.0005 for both groups combined); this was sustained at 2 months. A severity of pain index showed a statistically significant decrease for both groups. The 95% confidence interval for the difference between the number of leg cramps after vitamin E versus quinine treatment (95% confidence interval, -3.8, +3.2) suggests similar efficacy. Quinine and vitamin E were effective treatments for leg cramps in these patients. Considering the potential toxicity of quinine, vitamin E is recommended as the initial treatment of choice for patients on dialysis with leg cramps.

PMID 1457907
P S Connolly, E A Shirley, J H Wasson, D W Nierenberg
Treatment of nocturnal leg cramps. A crossover trial of quinine vs vitamin E.
Arch Intern Med. 1992 Sep;152(9):1877-80.
Abstract/Text OBJECTIVE: This study compared the efficacy and safety of quinine sulfate, vitamin E, and placebo in the treatment of nocturnal leg cramps.
DESIGN: A random-order, double-blind, placebo-controlled crossover trial was performed.
SETTING: The study was conducted at the Veterans Affairs Medical Center, White River Junction, Vt.
PARTICIPANTS: Twenty-seven male veterans, aged 38 to 73 years, who experienced at least six leg cramps per month were recruited through the general medicine walk-in clinic or were referred from other clinics. Fifty-five subjects were contacted, 30 were enrolled consecutively, and 27 completed the study.
INTERVENTION: Subjects received, in random order, quinine sulfate (200 mg at supper and 300 mg at bedtime), vitamin E (800 U at bedtime), or placebo for 4-week periods. These periods were separated by 4-week washout intervals.
OUTCOME MEASURES: Patients reported cramp frequency, severity, and sleep disturbance caused by cramps.
RESULTS: Compared with treatment with placebo, quinine reduced the frequency of cramps and sleep disturbance, but not the average cramp severity. Thirteen of 27 patients had at least a 50% reduction in the number of cramps while receiving quinine; the response was usually seen within 3 days. There was evidence of a mild increase in side effects while subjects received quinine. Vitamin E was not effective in reducing leg cramp frequency, severity, or sleep disturbance.
CONCLUSIONS: Quinine sulfate, but not vitamin E, is superior to placebo in the treatment of nocturnal leg cramps.

PMID 1520054
L O Dahle, G Berg, M Hammar, M Hurtig, L Larsson
The effect of oral magnesium substitution on pregnancy-induced leg cramps.
Am J Obstet Gynecol. 1995 Jul;173(1):175-80.
Abstract/Text OBJECTIVE: Our purpose was to determine whether women with pregnancy-related leg cramps would benefit from oral magnesium supplementation.
STUDY DESIGN: Seventy-three women with pregnancy-related leg cramps were interviewed about their symptoms in a prospective, double-blind, randomized trial. Initial serum magnesium levels and diurnal magnesium excretion was determined in 50% of the patients. Oral magnesium or placebo was given for 3 weeks, after which new interviews and laboratory analyses were performed.
RESULTS: Serum magnesium levels in these patients were at or below the lower reference limit, as is also often the case in healthy pregnant patients. Oral magnesium substitution decreased leg cramp distress (p < 0.05 compared with the placebo group, p < 0.001 compared with initial complaints), but did not significantly increase serum magnesium levels, excess magnesium being excreted as measured by an increase in urinary magnesium levels (p < 0.002).
CONCLUSION: Oral magnesium supplementation seems to be a valuable therapeutic tool in the treatment of pregnancy-related leg cramps.

PMID 7631676
R Frusso, M Zárate, F Augustovski, A Rubinstein
Magnesium for the treatment of nocturnal leg cramps: a crossover randomized trial.
J Fam Pract. 1999 Nov;48(11):868-71.
Abstract/Text BACKGROUND: Nocturnal leg cramps are a common health problem in the ambulatory setting. Our objective was to evaluate the efficacy of magnesium in the treatment of nocturnal leg cramps.
METHODS: Our study was a crossover randomized double-blind placebo-controlled trial. We included patients from a large university-based ambulatory clinic in Buenos Aires, Argentina, with at least 6 cramps during the previous month. A total of 93 subjects took part in a 4-week washout period with placebo. Those who were still eligible (n = 45) were randomized to receive either (1) an oral dose of 900 mg magnesium citrate twice daily for 1 month, followed by a matching placebo for 1 month, or (2) the placebo first, followed by magnesium. Both groups had a 4-week washout period with placebo between each treatment month. Forty-two patients completed the 4-month study. The main outcome was the number of nocturnal leg cramps, and the secondary outcomes were duration, severity, and sleep disorders caused by those cramps.
RESULTS: There were no significant differences between magnesium and placebo in any of the evaluated outcomes. The mean number of cramps was 11.1 (standard deviation [SD] +/- 7.3) for placebo versus 11.8 (SD +/- 7.6) for magnesium (P = .59). We observed a significant period-effect bias: All patients improved over time regardless of the treatment sequence they received.
CONCLUSIONS: Magnesium was not effective for the treatment of nocturnal leg cramps. The period-effect bias probably occurred because of a combination of the natural history of this condition, a regression to the mean, and a true placebo effect.

PMID 10907623
Christine Roffe, Sheila Sills, Peter Crome, Peter Jones
Randomised, cross-over, placebo controlled trial of magnesium citrate in the treatment of chronic persistent leg cramps.
Med Sci Monit. 2002 May;8(5):CR326-30.
Abstract/Text BACKGROUND: Nocturnal leg cramps are common and distressing. The only treatment of proven effectiveness is quinine, but this has a number of side effects. Magnesium salts have been shown to reduce leg cramp distress in pregnancy. This study tests whether magnesium citrate is effective in the treatment of leg cramps in non-pregnant individuals by conducting in a randomised, double-blind, cross-over placebo-controlled trial.
MATERIAL/METHODS: Volunteers suffering regular leg cramps were recruited. Magnesium citrate equivalent to 300 mg magnesium and matching placebo were given for 6 weeks each. The number of cramps recorded in the cramp diary during the final 4 weeks of magnesium and placebo treatment, severity and duration of cramps and the participants' subjective assessment of effectiveness were analysed.
RESULTS: In subjects who started with placebo (n=29) the median (95% CI) number of cramps was 9 (6-17) on placebo and 5 (4-8) on magnesium. For the group starting with magnesium (n=17) the median no of cramps was 9 (5-13) on magnesium and 8 (4-14) on placebo. There was no significant carry-over effect (p=0.88), but a highly significant period effect (p=0.008). There was a trend towards less cramps on magnesium (p=0.07). There was no difference in cramp severity and duration between the groups. Significantly more subjects thought that the treatment had helped after magnesium than after placebo 36 (78%) and 25 (54%) respectively, (p=0.03). Diarrhoea was recorded as a side effect of magnesium.
CONCLUSIONS: The results suggest that magnesium may be effective in treatment of nocturnal leg cramps. Further evaluation is recommended.

PMID 12011773
N Baltodano, B V Gallo, D J Weidler
Verapamil vs quinine in recumbent nocturnal leg cramps in the elderly.
Arch Intern Med. 1988 Sep;148(9):1969-70.
Abstract/Text In an open-labeled trial with eight elderly patients (aged 62 to 87 years) suffering from nocturnal leg cramps refractory to treatment with quinine sulfate, we ruled out other active disease processes and substituted verapamil hydrochloride therapy (120 mg at bedtime). Response to treatment was assessed by biweekly observations by the primary care physician and nightly by the research registered nurse for the entire duration of the trial, lasting eight weeks. Observations made and clinical conditions reported were indicative of improvement and disappearance of cramping when therapy was changed from quinine to verapamil. This noteworthy improvement in patients with recumbent nocturnal leg cramps is an important finding and merits further investigation.

PMID 3046538
W C Voon, S H Sheu
Diltiazem for nocturnal leg cramps.
Age Ageing. 2001 Jan;30(1):91-2.
Abstract/Text
PMID 11322688
M Serrao, P Rossi, P Cardinali, G Valente, L Parisi, F Pierelli
Gabapentin treatment for muscle cramps: an open-label trial.
Clin Neuropharmacol. 2000 Jan-Feb;23(1):45-9.
Abstract/Text To evaluate the efficacy and safety of gabapentin in the treatment of muscle cramps, we engaged an open-label trial with a group of 30 patients with frequent (> 5 cramps/week), stable, long-lasting cramps, associated with different diseases. Gabapentin was effective in reducing the frequency and severity of muscle cramps and associated sleep disturbances (clinical outcome measures) within the first 2 weeks of medication at 600 mg/d. At the 1 month control (mean dosage, 825 +/- 35 mg), almost every patient had responded to treatment and two thirds experienced a total remission of symptoms. After 3 months of therapy (mean dosage, 892 +/- 180 mg), cramps disappeared in 100% of patients and this benefit persisted as long as 6 months. Additionally, we evaluated in 10 patients the Cramps Threshold Frequency (CTF) (neurophysiological outcome measure) before and during gabapentin treatment. Gabapentin significantly increased the CTF, returning it to normal values. With the limitation of an open-label methodology, our clinical and neurophysiologic experience suggests that a gabapentin dose of 600-1200 mg/d would be helpful in the treatment of muscular cramps.

PMID 10682230
Richard S Bedlack, Daniel M Pastula, Jodi Hawes, Debra Heydt
Open-label pilot trial of levetiracetam for cramps and spasticity in patients with motor neuron disease.
Amyotroph Lateral Scler. 2009 Aug;10(4):210-5. doi: 10.1080/17482960802430773.
Abstract/Text Cramps and spasticity impair quality of life and function in patients with motor neuron diseases, and there are no proven treatments for these problems. We conducted a pilot trial to determine if treatment with levetiracetam was associated with a reduction in cramp severity, cramp frequency, tonic or phasic spasticity. We used an open-label repeated measures pilot trial of 20 patients, comparing cramp and spasticity scores over a 3-month baseline versus nine months on treatment. Cramp and spasticity scores were stable over a 3-month baseline. Shortly after starting levetiracetam, there was a significant reduction in cramp severity and frequency, which persisted for the duration of this year-long study. There was also a reduction in phasic but not tonic spasticity. Levetiracetam was well tolerated. Our results justify a placebo-controlled study of levetiracetam for treatment of cramps and spasticity in patients with motor neuron diseases, and suggest that this can be accomplished with a small number of subjects followed for a short time.

PMID 18821142
Satoshi Kuwabara, Sonoko Misawa, Noriko Tamura, Kazuaki Kanai, Akiyuki Hiraga, Kazue Ogawara, Miho Nakata, Takamichi Hattori
The effects of mexiletine on excitability properties of human median motor axons.
Clin Neurophysiol. 2005 Feb;116(2):284-9. doi: 10.1016/j.clinph.2004.08.014.
Abstract/Text OBJECTIVE: To investigate the effects of mexiletine, an analog of lidocaine, on excitability of human axons in vivo.
METHODS: Threshold tracking was used to measure multiple excitability indices (strength-duration time constant, rheobase, refractoriness, supernormality, and threshold electrotonus) in median motor axons of 20 patients with neuropathic pain or muscle cramping, before and 3 months after treatment with oral 300 mg mexiletine per day.
RESULTS: After treatment, there was a reduction in pain/muscle cramps, associated with decreased strength-duration time constants (P=0.01), increased rheobasic currents (P=0.06), and lower refractoriness (P=0.02), all of which were consistent with reduced nodal Na+ currents. Supernormality and threshold electrotonus did not change significantly. The changes in strength-duration properties suggest a decrease in persistent Na+ conductance. The lowered refractoriness after treatment might result from reduced transient Na+ currents, but the lack of change in supernormality and threshold electrotonus was not consistent with this hypothesis.
CONCLUSIONS: Oral mexiletine in a dosage of 300 mg daily suppresses persistent Na+ currents in human motor axons.
SIGNIFICANCE: Measurements of the excitability indices can be used for non-invasive assessment and monitoring of the effects of mexiletine in patients with neuropathic pain or muscle cramps.

PMID 15661106
Michael D Weiss, Eric A Macklin, Zachary Simmons, Angela S Knox, David J Greenblatt, Nazem Atassi, Michael Graves, Nicholas Parziale, Johnny S Salameh, Colin Quinn, Robert H Brown, Jane B Distad, Jaya Trivedi, Jeremy M Shefner, Richard J Barohn, Alan Pestronk, Andrea Swenson, Merit E Cudkowicz, Mexiletine ALS Study Group
A randomized trial of mexiletine in ALS: Safety and effects on muscle cramps and progression.
Neurology. 2016 Apr 19;86(16):1474-81. doi: 10.1212/WNL.0000000000002507. Epub 2016 Feb 24.
Abstract/Text OBJECTIVE: To determine the safety and tolerability of mexiletine in a phase II double-blind randomized controlled trial of sporadic amyotrophic lateral sclerosis (SALS).
METHODS: Sixty participants with SALS from 10 centers were randomized 1:1:1 to placebo, mexiletine 300 mg/d, or mexiletine 900 mg/d and followed for 12 weeks. The primary endpoints were safety and tolerability. Secondary endpoints were pharmacokinetic study from plasma and CSF, ALS Functional Rating Scale-Revised (ALSFRS-R) score, slow vital capacity (SVC), and muscle cramp frequency and severity.
RESULTS: The only serious adverse event among active arm participants was one episode of imbalance. Thirty-two percent of participants receiving 900 mg of mexiletine discontinued study drug vs 5% on placebo (p = 0.026). Pharmacokinetic study demonstrated a peak plasma concentration 2 hours postdose and strong correlation between plasma and CSF (p < 0.001). Rates of decline of ALSFRS-R and SVC did not differ from placebo. Analysis of all randomized patients demonstrated significant reductions of muscle cramp frequency (300 mg: rate = 31% of placebo, p = 0.047; 900 mg: 16% of placebo, p = 0.002) and cramp intensity (300 mg: mean = 45% of placebo, p = 0.08; 900 mg: 25% of placebo, p = 0.005).
CONCLUSIONS: Mexiletine was safe at both doses and well-tolerated at 300 mg/d but adverse effects at 900 mg/d led to a high rate of discontinuation. Mexiletine treatment resulted in large dose-dependent reductions in muscle cramp frequency and severity. No effect on rate of progression was detected, but clinically important differences could not be excluded in this small and short-duration study.
CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that mexiletine is safe when given daily to patients with amyotrophic lateral sclerosis at 300 and 900 mg and well-tolerated at the lower dose.

© 2016 American Academy of Neurology.
PMID 26911633
Louise Rabbitt, Eamon C Mulkerrin, Shaun T O'Keeffe
A review of nocturnal leg cramps in older people.
Age Ageing. 2016 Aug 11;. doi: 10.1093/ageing/afw139. Epub 2016 Aug 11.
Abstract/Text Nocturnal leg cramps are common and troublesome, especially in later life, and have a significant impact on quality of life, particularly sleep quality. This article reviews the current state of knowledge regarding the diagnosis, frequency, pathophysiology and management of cramps. Recent evidence suggests that diuretic and long-acting beta-agonist therapy predispose to leg cramps. There is conflicting evidence regarding the efficacy of prophylactic stretching exercises in preventing cramps. Quinine remains the only medication proven to reduce the frequency and intensity of leg cramps. However, the degree of benefit from quinine is modest and the risks include rare but serious immune-mediated reactions and, especially in older people, dose-related side effects. Quinine treatment should be restricted to those with severe symptoms, should be subject to regular review and requires discussion of the risks and benefits with patients.

© The Author 2016. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
PMID 27515677
L Parisi, F Pierelli, G Amabile, G Valente, E Calandriello, F Fattapposta, P Rossi, M Serrao
Muscular cramps: proposals for a new classification.
Acta Neurol Scand. 2003 Mar;107(3):176-86. doi: 10.1034/j.1600-0404.2003.01289.x.
Abstract/Text Muscle cramps are involuntary, painful, sudden contractions of the skeletal muscles. They are present in normal subjects under certain conditions (during a strong voluntary contraction, sleep, sports, pregnancy) and in several pathologies such as myopathies, neuropathies, motoneuron diseases, metabolic disorders, hydroelectrolyte imbalances or endocrine pathologies. There has been considerable uncertainty in the literature regarding the classification and nomenclature of muscle cramps, both because the term "cramp" is used to indicate a variety of clinical features of muscles, leading to its use as an imprecise "umbrella" term that includes stiffness, contractures and local pain, and because the spectrum of the diseases in which it appears is wide. The purpose of the present study is to propose a simple classification to provide a framework to better recognize the full spectrum of phenomenology of muscle cramps.

PMID 12614310
Hayam K Shaker, Leslie Mackler, Timothy E Huber
Clinical inquiries. What is the diagnostic approach to a patient with leg cramps?
J Fam Pract. 2005 Sep;54(9):817-8.
Abstract/Text
PMID 16144599

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