Abstract
Introduction
Involuntary, localised leg cramps are common and typically affect the calf muscles at night.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of treatments for idiopathic leg cramps? What are the effects of treatments for leg cramps in pregnancy? We searched: Medline, Embase, The Cochrane Library, and other important databases up to September 2008 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 12 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: analgesics; anti-epileptic drugs; calcium salts; compression hosiery; magnesium salts; multivitamin and mineral supplements; quinine alone or with theophylline; sodium chloride; and stretching exercises.
Key Points
Involuntary, localised leg cramps are common and typically affect the calf muscles at night.
The causes of leg cramps are unclear, but risk factors include: pregnancy; exercise; salt and electrolyte imbalances; disorders affecting peripheral nerves, blood vessels, or muscles; renal dialysis; and some drugs.
Quinine reduces the frequency of idiopathic leg cramps at night compared with placebo, but we don’t know the optimal dose or length of treatment.
Adding theophylline to quinine may reduce the frequency of nocturnal leg cramps compared with quinine alone.
CAUTION
Quinine may be associated with cardiac arrhythmias, thrombocytopenia, and severe hypersensitivity reactions. It is a known teratogen and the risks are not outweighed by any potential benefits of its use in pregnancy.
We don’t know whether analgesics, anti-epileptic drugs, magnesium salts, vitamin E, stretching exercises, or compression hosiery reduce leg cramps.
We don’t know whether calcium salts, sodium chloride, or multivitamins and mineral supplements reduce leg cramps in pregnant women.
About this condition
Definition
Leg cramps are involuntary, localised, and usually painful skeletal muscle contractions, which commonly affect calf muscles. Leg cramps typically occur at night and usually last only seconds to minutes. Leg cramps may be idiopathic (of unknown cause) or may be associated with a definable process or condition such as pregnancy, renal dialysis, or venous insufficiency. This review does not currently cover leg cramps associated with renal dialysis or venous insufficiency.
Incidence/ Prevalence
Leg cramps are common and their incidence increases with age. About half of people attending a general medicine clinic have had leg cramps within 1 month of their visit, and over two-thirds of people over 50 years of age have experienced leg cramps.
Aetiology/ Risk factors
Little is known about the causes of leg cramps. Risk factors include pregnancy, exercise, electrolyte imbalances, salt depletion, renal dialysis, peripheral vascular disease (both venous and arterial), peripheral nerve injury, polyneuropathies, motor neurone disease, muscle diseases, and certain drugs. Other causes of acute calf pain include trauma, DVT (see review on thromboembolism), and ruptured Baker’s cyst.
Prognosis
Leg cramps may cause severe pain and sleep disturbance.
Aims of intervention
To reduce the frequency and severity of attacks of cramp, with minimal adverse effects of treatment.
Outcomes
Leg cramp symptoms (includes frequency, duration, severity of attacks, and number of disturbed nights), adverse effects of treatment.
Methods
Clinical Evidence search and appraisal September 2008. The following databases were used to identify studies for this systematic review: Medline 1966 to September 2008, Embase 1980 to September 2008, and The Cochrane Database of Systematic Reviews and Cochrane Central Register of Controlled Clinical Trials 2008, Issue 3 (1966 to date of issue). An additional search was carried out of the NHS Centre for Reviews and Dissemination (CRD) — for Database of Abstracts of Reviews of Effects (DARE) and Health Technology Assessment (HTA). We also searched for retractions of studies included in the review. Abstracts of the studies retrieved from the initial search were assessed by an information specialist. Selected studies were then sent to the contributor for additional assessment, using pre-determined criteria to identify relevant studies. Study design criteria for inclusion in this review were: published systematic reviews and RCTs in any language. RCTs could be open or blinded, and there was no minimum number of patients or length of follow-up required to include studies. At least 80% of the patients had to be followed up. We included systematic reviews of RCTs and RCTs where harms of an included intervention were studied applying the same study design criteria for inclusion as we did for benefits. In addition, we use a regular surveillance protocol to capture harms alerts from organisations such as the FDA and the UK Medicines and Healthcare products Regulatory Agency (MHRA), which are added to the reviews as required. To aid readability of the numerical data in our reviews, we round many percentages to the nearest whole number. Readers should be aware of this when relating percentages to summary statistics such as relative risks (RRs) and odds ratios (ORs). We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table). The categorisation of the quality of the evidence (high, moderate, low, or very low) reflects the quality of evidence available for our chosen outcomes in our defined populations of interest. These categorisations are not necessarily a reflection of the overall methodological quality of any individual study, because the Clinical Evidence population and outcome of choice may represent only a small subset of the total outcomes reported, and population included, in any individual trial. For further details of how we perform the GRADE evaluation and the scoring system we use, please see our website (www.clinicalevidence.com).
Table.
GRADE Evaluation of interventions for Leg cramps.
| Important outcomes | Leg cramp symptoms | ||||||||
| Studies (Participants) | Outcome | Comparison | Type of evidence | Quality | Consistency | Directness | Effect size | GRADE | Comment |
| What are the effects of treatments for idiopathic leg cramps? | |||||||||
| 9 (672) | Leg cramp symptoms | Quinine versus placebo | 4 | –2 | 0 | 0 | +1 | Moderate | Quality points deducted for incomplete reporting of results and inclusion of small RCTs with weak methods. Effect-size point added for RR <0.5 |
| 1 (164) | Leg cramp symptoms | Quinine plus theophylline versus placebo | 4 | –2 | 0 | –1 | 0 | Very low | Quality points deducted for sparse data and poor follow-up. Directness point deducted for uncertain assessment of outcome |
| 1 (164) | Leg cramp symptoms | Quinine plus theophylline versus quinine alone | 4 | –2 | 0 | –1 | 0 | Very low | Quality points deducted for sparse data and poor follow-up. Directness point deducted for uncertain assessment of outcome |
| 2 (113) | Leg cramp symptoms | Magnesium citrate versus placebo | 4 | –3 | 0 | 0 | 0 | Very low | Quality points deducted for sparse data, incomplete reporting of results, poor crossover methodology, and poor follow-up |
| 1 (27) | Leg cramp symptoms | Vitamin E versus placebo | 4 | –2 | 0 | –1 | 0 | Very low | Quality points deducted for sparse data and incomplete reporting of results. Directness point deducted for inclusion only of men |
| 1 (27) | Leg cramp symptoms | Vitamin E versus quinine | 4 | –2 | 0 | –1 | 0 | Very low | Quality points deducted for sparse data and uncertain crossover methodology. Directness point deducted for inclusion only of men |
| 1 (191) | Leg cramp symptoms | Stretching exercises versus passive non-stretching exercises | 4 | –2 | 0 | –1 | 0 | Very low | Quality points deducted for sparse data and no blinding. Directness point deducted for uncertain benefits from control treatment |
| What are the effects of treatments for leg cramps in pregnancy? | |||||||||
| 2 (102) | Leg cramp symptoms | Calcium salts versus no treatment or vitamin C placebo | 4 | –2 | –1 | –1 | 0 | Very low | Quality points deducted for sparse data and poor blinding. Consistency point deducted for conflicting results. Directness point deducted for uncertain benefits from control treatment |
| 1 (73) | Leg cramp symptoms | Magnesium salts versus placebo | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for sparse data and uncertain randomisation methodology |
| 1 (62) | Leg cramp symptoms | Multivitamin and mineral supplements versus placebo | 4 | –2 | 0 | –1 | 0 | Very low | Quality points deducted for sparse data and poor follow-up. Directness point deducted as study not designed to assess treatment for cramps |
We initially allocate 4 points to evidence from RCTs, and 2 points to evidence from observational studies. To attain the final GRADE score for a given comparison, points are deducted or added from this initial score based on preset criteria relating to the categories of quality, directness, consistency, and effect size. Quality: based on issues affecting methodological rigour (e.g., incomplete reporting of results, quasi-randomisation, sparse data [<200 people in the analysis]). Consistency: based on similarity of results across studies. Directness: based on generalisability of population or outcomes. Effect size: based on magnitude of effect as measured by statistics such as relative risk, odds ratio, or hazard ratio.
Glossary
- Low-quality evidence
Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
- Moderate-quality evidence
Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
- Very low-quality evidence
Any estimate of effect is very uncertain.
Compression hosiery for venous leg ulcers
Disclaimer
The information contained in this publication is intended for medical professionals. Categories presented in Clinical Evidence indicate a judgement about the strength of the evidence available to our contributors prior to publication and the relevant importance of benefit and harms. We rely on our contributors to confirm the accuracy of the information presented and to adhere to describe accepted practices. Readers should be aware that professionals in the field may have different opinions. Because of this and regular advances in medical research we strongly recommend that readers' independently verify specified treatments and drugs including manufacturers' guidance. Also, the categories do not indicate whether a particular treatment is generally appropriate or whether it is suitable for a particular individual. Ultimately it is the readers' responsibility to make their own professional judgements, so to appropriately advise and treat their patients. To the fullest extent permitted by law, BMJ Publishing Group Limited and its editors are not responsible for any losses, injury or damage caused to any person or property (including under contract, by negligence, products liability or otherwise) whether they be direct or indirect, special, incidental or consequential, resulting from the application of the information in this publication.
References
- 1.Hall AJ. Cramp and salt balance in ordinary life. Lancet 1947;3:231–233. [DOI] [PubMed] [Google Scholar]
- 2.Man-Son-Hing M, Wells G, Lau A. Quinine for nocturnal leg cramps: a meta-analysis including unpublished data. J Gen Intern Med 1998;13:600–606. Search date 1997; primary sources Medline, Embase, Current Contents, and contact with authorities. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.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. [PMC free article] [PubMed] [Google Scholar]
- 4.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. [PMC free article] [PubMed] [Google Scholar]
- 5.Food and Drug Administration. FDA Medwatch Safety Alert. Quinine products. 2006. Available at: http://www.fda.gov/medwatch/safety/2006/safety06.htm#Quinine (last accessed 20 July 2010). [Google Scholar]
- 6.MHRA. Drug analysis print. Drug name: Quinine. Report run date 23 November 2008. MHRA Available at: http://www.mhra.gov.uk/home/groups/public/documents/sentineldocuments/dap_1229939299608.pdf (last accessed 20 July 2010). [Google Scholar]
- 7.McGee SR. Muscle cramps. Arch Intern Med 1990;150:511–518. [PubMed] [Google Scholar]
- 8.Gorlich HD, Gablez VE, Steinberg HW. Treatment of nocturnal leg cramps. A multicenter double blind, placebo controlled comparison between the combination of quinine and theophylline ethylene diamine with quinine. Arzneimittelforschung 1991;41:167–175. [In German] [PubMed] [Google Scholar]
- 9.Frusso R, Zarate M, Augustovski F, et al. Magnesium for the treatment of nocturnal leg cramps: a crossover randomized trial. J Fam Pract 1999;48:868–871. [PubMed] [Google Scholar]
- 10.Roffe C, Sills S, Crome P, et al. Randomised, cross-over, placebo controlled trial of magnesium citrate in the treatment of chronic persistent leg cramps. Med Sci Monit 2002;8:CR326–CR330. [PubMed] [Google Scholar]
- 11.Connolly PS, Shirley EA, Wasson JH, et al. Treatment of nocturnal leg cramps: a crossover trial of quinine vs vitamin E. Arch Intern Med 1992;152:1877–1880. [PubMed] [Google Scholar]
- 12.Young GL, Jewell D. Interventions for leg cramps in pregnancy. In: The Cochrane Library, Issue 3, 2008. Chichester, UK: John Wiley & Sons, Ltd. Search date 2001. 11869565 [Google Scholar]
- 13.Hammar M, Larsson L, Tegler L. Calcium treatment of leg cramps in pregnancy. Acta Obstet Gynecol Scand 1981;60:345–347. [DOI] [PubMed] [Google Scholar]
- 14.Hammar M, Berg G, Solheim F, et al. Calcium and magnesium status in pregnant women. A comparison between treatment with calcium and vitamin C in pregnant women with leg cramps. Int J Vitam Nutr Res 1987;57:179–183. [PubMed] [Google Scholar]
- 15.
- 16.Dahle LO, Berg G, Hammar M, et al. The effect of oral magnesium substitution on pregnancy-induced leg cramps. Am J Obstet Gynecol 1995;173:175–180. [DOI] [PubMed] [Google Scholar]
- 17.Thauvin E, Fusselier M, Arnaud J, et al. Effects of a multivitamin mineral supplement on zinc and copper status during pregnancy. Biol Trace Elem Res 1992;32:405–414. [DOI] [PubMed] [Google Scholar]
- 18.Robinson M. Cramps in pregnancy. J Obstet Gynaecol Br Commonw 1947;54:826–829. [DOI] [PubMed] [Google Scholar]
- 19.Shahraki AD. Effects of vitamin E, calcium carbonate and milk of magnesium on muscular cramps in pregnant women. J Med Sci 2006;6:979–983. [Google Scholar]
- 20.Mokhtari M, Yaghmaie M, Mohammadi M. The comparison of the therapeutic effect of vitamin E on leg cramps during pregnancy. Obstet Gynecol Infert 2002;5:42–46. [Google Scholar]