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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 January 2014 (BMJ 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 16 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; diltiazem; magnesium salts; multivitamin and mineral supplements; quinine; sodium chloride; stretching exercises; verapamil; vitamin B6 (pyridoxine); and vitamin E.
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 or blood vessels, renal dialysis, and some drugs.
This review examined RCTs on the effects of interventions on idiopathic leg cramps and leg cramps in pregnancy. Overall, many of the RCTs were small and had weak methods.
Idiopathic leg cramps:
Quinine reduces the frequency of idiopathic leg cramps at night compared with placebo.
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. It may also be associated with fatal adverse effects.
Leg cramps are involuntary, localised, and usually painful skeletal muscle contractions, which commonly affect calf muscles but can occur anywhere in the leg from foot up to the thigh. 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 more than two-thirds of people aged over 50 years 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, and certain drugs (including beta agonists and potassium-sparing diuretics). 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 leg cramp, with minimal adverse effects of treatment.
Outcomes
Leg cramp symptoms (e.g., frequency, duration, severity of attacks, and number of disturbed nights), adverse effects.
Methods
BMJ Clinical Evidence search and appraisal January 2014. The following databases were used to identify studies for this systematic review: Medline 1966 to January 2014, Embase 1980 to January 2014, and The Cochrane Database of Systematic Reviews 2014, issue 1 (1966 to date of issue). Additional searches were carried out in the Database of Abstracts of Reviews of Effects (DARE) and the Health Technology Assessment (HTA) database. We also searched for retractions of studies included in the review. Titles and abstracts were identified in an initial search, run by an information specialist, which an evidence scanner then assessed against predefined criteria. An evidence analyst then assessed full texts for potentially relevant studies against predefined criteria. An expert contributor was consulted on studies selected for inclusion. An evidence analyst then extracted all data relevant to the review. Study design criteria for inclusion in this review were published RCTs or systematic reviews of RCTs in the English language. RCTs could be open or blinded, and there was no minimum length of follow-up required to include studies. There was no minimum number of individuals to include studies, but at least 80% of individuals had to be followed up. We included RCTs and systematic reviews of RCTs where harms of an included intervention were assessed, applying the same study design criteria for inclusion as we did for benefits. In addition, all serious adverse effects, or those adverse effects that were reported as statistically significant, were data extracted for inclusion in the review. Prespecified adverse effects identified as being clinically important were reported, even if the results were not significant. In addition, we used a regular surveillance protocol to capture harms alerts from organisations such as the FDA and the 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?
1 (12)
Leg cramp symptoms
Diltiazem versus placebo
4
–3
0
0
0
Very low
Quality points deducted for weak methods, sparse data, and incomplete reporting.
4 (213)
Leg cramp symptoms
Magnesium salts versus placebo
4
–1
0
–1
0
Low
Quality point deducted for weak methods; directness point deducted for uncertainty about included population (skeletal cramps)
14 (at least 982)
Leg cramp symptoms
Quinine versus placebo
4
–1
–1
0
0
Low
Quality point deducted for weak methods; consistency point deducted for statistical heterogeneity
1 (94)
Leg cramp symptoms
Stretching exercises versus passive non-stretching exercises
4
–2
0
–2
0
Very low
Quality points deducted for weak methods and sparse data; directness points deducted for choice given to participants of treatment at 6 weeks, and use of co-intervention (quinine)
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 restricted population (inclusion only of men)
4 (at least 513)
Leg cramp symptoms
Vitamin E versus quinine
4
–1
–1
–1
0
Very low
Quality point deducted for weak methods; consistency point deducted for statistical heterogeneity; directness point deducted for uncertainty about included population (skeletal cramps)
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 weak methods; consistency point deducted for conflicting results; directness point deducted for uncertain benefits from control treatment
3 (202)
Leg cramp symptoms
Magnesium salts versus placebo or no treatment
4
–2
0
–1
0
Very low
Quality points deducted for weak methods and incomplete reporting of results; directness point deducted for unclear outcomes in one RCT
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.
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.
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We found insufficient evidence on the effects of diltiazem on idiopathic leg cramps.
Benefits and harms
Diltiazem versus placebo:
We found one systematic review (search date 2008), which found one small, weak crossover RCT comparing diltiazem with placebo. The results of this study should be interpreted with caution (see Comment).
Leg cramp symptoms
Diltiazem compared with placebo We don't know whether diltiazem is more effective than placebo at reducing idiopathic leg cramps (very low-quality evidence).
Ref (type)
Population
Outcome, Interventions
Results and statistical analysis
Effect size
Favours
Leg cramp symptoms
Systematic review
13 people experiencing 2 or more leg cramps per week
Number of cramps
2-week treatment phase
with diltiazem hydrochloride with placebo Absolute results not reported
P = 0.04
Caution should be taken in interpreting this result (see Comment)
Effect size not calculated
diltiazem
Systematic review
13 people experiencing 2 or more leg cramps per week
Intensity of leg cramps (1–3 point scale, measure of intensity not further defined)
with diltiazem hydrochloride with placebo Absolute results not reported
P = 0.347
Caution should be taken in interpreting this result (see Comment)
The review included one small crossover RCT (13 people). The RCT had been reported as a letter to the editor, and the review did not report further details on methods. The RCT reported results for 12/13 (92%) of included participants, and one person who started on medication for high blood pressure was excluded from the analysis. Baseline characteristics were not reported, people were given allocated treatments for a 2-week period with a 2-week washout period, and results were not reported beyond 2 weeks. It was unclear how people in the trial had been recruited. As detailed methods were not presented, results from this trial should be interpreted with great caution.
Substantive changes
Diltiazem for idiopathic leg cramps New option. One systematic review and one small crossover RCT added. Categorised as 'unknown effectiveness'.
We don't know whether magnesium citrate is more effective than placebo at reducing idiopathic leg cramps at 4 weeks.
Benefits and harms
Magnesium salts versus placebo:
We found one systematic review (search date 2011), which included four RCTs. Only one RCT specified leg cramps (45 people) while the other three RCTs specified that the included population were 'rest cramp sufferers' (46 people, 73 people, 40 people). The review reported that the RCTs involved the treatment of idiopathic cramps in older adults "most of whom are presumed to have been suffering from nocturnal leg cramps". One RCT was unpublished, and further unpublished data were made available to the review on two other RCTs. Two RCTs were crossover in design. In one RCT (73 people), only data from the first period of the study were used because of a large difference in treatment effect resulting from sequence allocation (see Further information on studies). Three RCTs gave magnesium orally, while one RCT (46 people) gave magnesium via intravenous infusion.
Leg cramp symptoms
Magnesium citrate compared with placebo Magnesium citrate may be no more effective than placebo at reducing idiopathic leg cramps at 4 weeks (low-quality evidence).
Ref (type)
Population
Outcome, Interventions
Results and statistical analysis
Effect size
Favours
Leg cramp symptoms
Systematic review
People with cramps 2 RCTs in this analysis
Percentage change in cramp frequency
from baseline to 4 weeks
with magnesium with placebo
Mean difference –3.93
95% CI –21.12 to +13.26
P = 0.65
Not significant
Systematic review
People with cramps 2 RCTs in this analysis
Proportion of people with at least 25% reduction in cramp frequency
4 weeks
24/42 (57%) with magnesium 27/41 (66%) with placebo
Risk difference –0.08
95% CI –0.28 to +0.12
P = 0.44
Not significant
Systematic review
People with cramps 4 RCTs in this analysis
Number of cramps per week
4 weeks
with magnesium with placebo
Mean difference +0.01
95% CI –0.52 to +0.55
P = 0.96
Not significant
Systematic review
People with cramps 3 RCTs in this analysis
Cramp intensity (pain) on a 3-point scale (1 = mild; 2 = moderate; 3 = severe)
4 weeks
with magnesium with placebo
Mean difference –0.04
95% CI –0.18 to +0.11
P = 0.62
The risk of selection bias (randomisation or allocation) was unclear in three of the four RCTs. In the fourth RCT, randomisation blocks were either unbalanced initially or became so because of non-completers, and data from only the first period of this crossover trial was used. Blinding was unclear in two RCTs, one RCT had a dropout rate of 37%, and one unpublished study was at high risk of bias for selective reporting because only a subset of outcomes were available.
Comment
The systematic review we found concluded that it was unlikely that magnesium supplementation provides clinically meaningful cramp prophylaxis to older adults experiencing skeletal muscle cramps.
Substantive changes
Magnesium salts for idiopathic leg cramps One systematic review added. Categorisation unchanged (unknown effectiveness).
Quinine may reduce the frequency of idiopathic leg cramps at night compared with placebo.
CAUTION Quinine may be associated with severe (including fatal) adverse effects, including 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.
Benefits and harms
Quinine versus placebo:
We found two systematic reviews, both of which included unpublished data.
The first review (search date 1997) only included RCTs on nocturnal leg cramps and pooled data. The second and later review (search date 2010) included muscle cramps generally, including cramps in any body part and from any cause. It also pooled data and reported slightly different outcomes. We have, therefore, reported both reviews. The second review reported that 20 RCTs investigating idiopathic leg cramps were "most often in elderly participants suffering from nocturnal leg cramps". However, we have reported where the included population in the RCTs was reported as 'muscle cramps' in the trial description (see Further information on studies).
Leg cramp symptoms
Quinine compared with placebo Quinine may be more effective than placebo at reducing idiopathic leg cramps at 2 to 4 weeks (low-quality evidence).
Ref (type)
Population
Outcome, Interventions
Results and statistical analysis
Effect size
Favours
Leg cramp symptoms
Systematic review
People with nocturnal leg cramps 7 RCTs in this analysis
Reduction in frequency of nocturnal leg cramps
4 weeks
with quinine with placebo Absolute results reported graphically
ARR for quinine v placebo 3.60 cramps/month
95% CI 2.15 to 5.05 cramps/month
RR 0.21
95% CI 0.12 to 0.30
Moderate effect size
quinine
Systematic review
People with cramps 14 RCTs in this analysis
Difference in number of cramps (occurring day or night)
2-week treatment period
with quinine with placebo
Mean difference in the number of cramps –1.81
95% CI –1.42 to –2.20
P <0.00001
Significant heterogeneity in analysis (I2 = 89%; P value for heterogeneity <0.0001)
See Further information on studies
Effect size not calculated
quinine
Systematic review
People with cramps 7 RCTs in this analysis
Difference in cramp intensity (measured on a 3-point scale where 1 = mild pain; 2 = moderate pain; 3 = severe pain)
with quinine with placebo
Cramp intensity –0.12
95% CI –0.20 to –0.05
P = 0.0011
Effect size not calculated
quinine
Systematic review
People with leg cramps 2 RCTs in this analysis
Change in cramp duration (minutes)
with quinine with placebo
Change in duration –1.35 minutes
95% CI –4.00 to +1.30 minutes
P = 0.32
The review reported that of 6 further RCTs that did not present data in a form that allowed them to be added to the meta-analysis, 5 found no significant difference with regard to cramp duration
Not significant
Systematic review
People with cramps 7 RCTs in this analysis
Difference in number of cramp days
2 weeks
with quinine with placebo
Cramp days –1.15
95% CI –1.93 to –0.38
P = 0.0036
Significant heterogeneity in analysis (I2 = 86%; P <0.00001); this was following the exclusion of 1 RCT which was causing heterogeneity; further sensitivity analysis not reported
Of the eight included RCTs, seven were crossover. The review noted in a sub-group analysis that the point estimate of benefit for quinine was larger when the analysis was confined to published trials than seen when the analysis was confined to unpublished trials. It noted that the treatment periods of all the unpublished studies was 1 to 2 weeks, and that this may have not been long enough to show any full benefit.
General Of the 23 included studies, 13 RCTs were crossover, nine were parallel in design, and one was an 'N-of-1' trial. Five RCTs were unpublished (acquired via the FDA), including the two largest RCTs (556 people; 205 people) which contributed 58% of all the participants in the meta-analysis. The review reported that, in total, 20 RCTs investigated idiopathic muscle cramps, most often older participants with nocturnal leg cramps (absolute numbers in this group not reported). Methods The review reported that quality varied considerably, with only 8/23 (33%) studies describing the method of randomisation, and 8/23 (33%) describing how allocation was concealed. It reported that almost all of the included trials had methodological limitations, including inadequate washout periods, small number of participants, inadequate explanation of methods, and poor statistical presentation. Heterogeneity For cramp number, a sensitivity analysis excluding one RCT (30 people) that used a higher dose of quinine and only included men did not resolve the heterogeneity (cramp number –2.45, 95% CI –1.36 to –3.54; I2 = 71%; P value for heterogeneity = 0.00003). Further sensitivity analysis excluding trials with high/unclear risk of bias for allocation sequence generation, allocation concealment, and blinding resulted in changes to the overall heterogeneity (I2 = 50%, 67%, and 91%, respectively). In general, the review reported that significant unexplained heterogeneity was notable in many of the meta-analyses. Adverse effects The review noted that quinine had been implicated in accidental and intentional poisoning, and that many of the included trials failed to elaborate on adverse events, which lies at the heart of the debate on quinine's risk-benefit ratio.
Comment
The review commented on the difference between the US and Europe in the use of quinine for muscle cramps. It reported that it could only be used off-label in the US, while in the UK quinine was used (although with strict advice), and in Germany it could be bought over the counter. The BNF states that, because of potential toxicity, quinine is not recommended for routine treatment. One review concluded that quinine "should only be considered when cramps are very disabling, no other agents relieve symptoms, and there is careful monitoring of side effects".
Dose and length of treatment
We found one open-label RCT (191 people aged at least 60 years who had received quinine for leg cramps in the previous 3 months), which did not directly assess the duration of treatment, but assessed stretching exercises, also compared advice to stop taking quinine for 6 weeks versus no advice. All participants who were advised to stop quinine were told that, at 6 weeks, they could decide whether to resume medication. The RCT found that, at 12 weeks, significantly more people who had been advised to stop quinine had stopped medication compared with people not receiving advice (OR 3.32, 95% CI 1.37 to 8.06; absolute numbers not reported).
Drug safety alert
An FDA alert in 2012 highlighted the serious risks associated with using quinine to prevent or treat nocturnal leg cramps (www.fda.gov). It highlighted that it is not considered safe and effective for the treatment or prevention of leg cramps and is an 'off-label' (non-FDA approved) use. It reported that quinine is associated with thrombocytopenia, hypersensitivity reactions, and QT prolongation. In addition, the thrombocytopenia includes immune thrombocytopenia, haemolytic uraemic syndrome, and thrombotic thrombocytic purpura with associated renal insufficiency. There have also been reports of fatalities and renal insufficiency requiring haemodialysis. Quinine is highly toxic in overdose.
Clinical guide
The results of the RCT assessing advice to stop taking quinine suggest that it is possible to advise people who have been taking quinine long term that they may be able to stop medication without any increase in cramps. Quinine is a known teratogen in high doses and, for treatment of cramp, the risk outweighs any possible benefit in pregnancy. Elevated quinine levels may cause cinchonism, a syndrome caused by derivatives of cinchona bark. This usually presents with nausea, vomiting, headache, tinnitus, deafness, vertigo, and visual disturbance.
Substantive changes
Quinine for idiopathic leg cramps One systematic review added. Categorisation unchanged (trade-off between benefits and harms).
We don't know whether stretching exercises are effective at reducing idiopathic leg cramps.
Benefits and harms
Stretching exercises versus passive non-stretching exercises:
We found one systematic review (search date 2011), which included one RCT (191 people). The RCT included people who had, and had not, been advised to discontinue quinine (which had been taken for the 3 months prior to trial commencement). There was no washout period for those discontinuing quinine. In order to avoid confounding, the review only included the 97 participants advised to continue taking quinine in its analysis, and also obtained further unpublished data from the original trial authors.
Leg cramp symptoms
Stretching exercises compared with passive non-stretching exercises We don't know whether stretching 'standing' exercises are more effective than passive non-stretching 'lying' exercises (placebo stretching exercise) at reducing idiopathic leg cramps (very low-quality evidence).
Ref (type)
Population
Outcome, Interventions
Results and statistical analysis
Effect size
Favours
Leg cramp symptoms
Systematic review
People with leg cramps Data from 1 RCT
Mean number of cramps
last 4 weeks of 12-week follow-up
10.02 with calf muscle stretching 'standing' 8.83 with passive non-stretching 'lying' exercise (placebo stretching)
Mean difference +1.19
95% CI –5.86 to +8.25
See Further information on studies
No data from the following reference on this outcome.
Further information on studies
The review noted that, after 6 weeks, participants in both the stretching exercise and passive 'lying' exercise (placebo stretching) groups were allowed to swap or discontinue stretching treatments and to decide whether or not to continue taking quinine. The review excluded the other participants who had been advised to discontinue quinine at the start of the trial in order to avoid the confounding effects of changing interventions. It reported that the RCT was at high risk of reporting bias and, as participants were allowed to discontinue or swap treatments at 6 weeks, the results at 12 weeks might not reflect the effects of the intervention at baseline. It also reported that the study design did not reflect clinical practice and interpretations of results are limited as it was impossible to isolate the effects of the intervention assigned at baseline.
Comment
Clinical guide
It has been widely assumed that stretching exercises would reduce the number and severity (or both) of cramps, possibly because of the common experience that stretching a muscle aborts an actual attack. Although the evidence we found seemed to show no benefit, it is possible that the passive 'lying' exercises were effective, and the researchers had inadvertently found an active sham treatment.
Substantive changes
Stretching exercises for idiopathic leg cramps One systematic review added. Categorisation unchanged (unknown effectiveness).
We don’t know whether vitamin E reduces idiopathic leg cramps.
Benefits and harms
Vitamin E versus placebo:
We found one systematic review (search date 2008), which included one crossover RCT. We have reported directly from the RCT.
Leg cramp symptoms
Vitamin E compared with placebo We don't know whether vitamin E is more effective than placebo at reducing idiopathic leg cramps in men (very low-quality evidence).
Ref (type)
Population
Outcome, Interventions
Results and statistical analysis
Effect size
Favours
Leg cramp symptoms
RCT Crossover design 3-armed trial
27 men In review
Median number of nights with leg cramps
14 nights with vitamin E 15 nights with placebo
We found one systematic review (search date 2010), which included four RCTs, and included both published and unpublished data (see option on Quinine for idiopathic leg cramps).
Leg cramp symptoms
Vitamin E compared with quinine We don’t know whether vitamin E and quinine differ in effectiveness at reducing idiopathic leg cramps (very low-quality evidence).
Ref (type)
Population
Outcome, Interventions
Results and statistical analysis
Effect size
Favours
Leg cramp symptoms
Systematic review
People with leg cramps 3 RCTs in this analysis
Difference in number of cramps
2 weeks
with quinine with vitamin E Absolute results not reported
Number of cramps –0.24
95% CI –1.29 to +0.81
P = 0.66
This analysis excluded 1 RCT that used a higher dose of quinine and included only men, and which increased heterogeneity (I2 of 94% reduced to 29% on exclusion)
Not significant
Systematic review
People with leg cramps 3 RCTs in this analysis
Difference in cramp intensity
with quinine with vitamin E
Cramp intensity –0.06
95% CI –0.17 to +0.04
P = 0.24
This analysis excluded 1 RCT that used a higher dose of quinine and included only men
Not significant
Systematic review
People with leg cramps 2 RCTs in this analysis
Difference in number of cramp days
2 weeks
with quinine with vitamin E
Cramp days –0.28
95% CI –0.98 to +0.43
P = 0.44
This analysis excluded 1 RCT that used a higher dose of quinine and included only men, and which increased heterogeneity (I2 of 98% reduced to 48% on exclusion)
Of the four included RCTs, all had unclear sequence allocation, and three had unclear allocation concealment. One crossover RCT had a short washout period, and another RCT had a high dropout rate (27%). Two of the four RCTs were previously unpublished.
Comment
None.
Substantive changes
Vitamin E for idiopathic leg cramps Two systematic reviews added.
Categorisation unchanged (unknown effectiveness).
We don’t know whether calcium salts reduce leg cramps in pregnant women.
Benefits and harms
Calcium salts versus no treatment or vitamin C placebo:
We found one systematic review (search date 2011), which included two RCTs.
We have reported directly from the RCTs.
Leg cramp symptoms
Calcium salts compared with no treatment or vitamin C placebo We don’t know how calcium salts compare with no treatment or with vitamin C 'placebo' in treating leg cramps in pregnant women (very low-quality evidence).
Ref (type)
Population
Outcome, Interventions
Results and statistical analysis
Effect size
Favours
Leg cramp symptoms
RCT
42 pregnant women In review
Women with persisting leg cramps
2/21 (10%) with calcium 18/21 (86%) with no treatment
OR 0.05
95% CI 0.02 to 0.17
See Comment for details of methodological limitations
Large effect size
calcium
RCT
60 pregnant women In review
Women with persisting leg cramps
11/30 (37%) with calcium 8/30 (27%) with vitamin C placebo
OR 1.58
95% CI 0.54 to 4.63
See Comment for details of methodological limitations
No data from the following reference on this outcome.
Further information on studies
The systematic review was updated from a previous search date of 2001 to 2011, but it did not include any new data further to the two RCTs identified previously. It identified one further study (a report at an annual congress in 1998) that was awaiting further assessment. The review noted that the first RCT did not state the method of allocation and was at high risk for allocation concealment, as was the second RCT. Neither RCT reported on adverse effects.
Comment
The lack of a placebo group in the first RCT makes the results difficult to interpret, as the benefits seen with calcium salts might have been due in part to a placebo effect. In the second RCT, vitamin C was used as a placebo, as it was not known to have an effect on leg cramps. However, there was a marked difference in the response of the control group in the two included RCTs. In the first RCT, 18/21 (86%) women with no treatment had no improvement in cramps. In the second RCT, 8/30 (27%) women with vitamin C had no improvement. It is unclear whether this difference was due to a beneficial effect of vitamin C on leg cramps, differences between the population in the RCTs, or another cause.
Substantive changes
Calcium salts for leg cramps in pregnancy One systematic review updated. Categorisation unchanged (unknown effectiveness).
We don't know whether magnesium is more effective than placebo or no treatment at reducing leg cramps in pregnant women, as the evidence is weak and contradictory.
Benefits and harms
Magnesium salts versus placebo or no treatment:
We found one systematic review (search date 2011), which included three RCTs that "involved treatment of pregnancy associated leg cramps". The review could not pool data because of the different outcome measures used in the trials. We have, therefore, reported the results of RCTs individually.
Leg cramp symptoms
Magnesium salts compared with placebo or no treatment We don't know whether magnesium is more effective than placebo or no treatment at reducing leg cramps in pregnant women as we found inconsistent evidence (very low-quality evidence).
Ref (type)
Population
Outcome, Interventions
Results and statistical analysis
Effect size
Favours
Leg cramp symptoms
Systematic review
73 pregnant women Data from 1 RCT
Frequency of symptoms, from initial average of every other day to:
"1 to 2 times a week" with magnesium "every 3 days" with placebo Absolute results not reported
P <0.05
The review noted that this outcome measure did not correlate with the 5-point ordinal scale used to measure this outcome
Effect size not calculated
magnesium
Systematic review
73 pregnant women Data from 1 RCT
Participant evaluation of treatment, women self-rating they had "improved considerably" or "become asymptomatic"
27/34 (79%) with magnesium 14/35 (40%) with placebo
P = 0.0002
Effect size not calculated
magnesium
Systematic review
45 pregnant women with rest cramps Data from 1 RCT
Mean number of days and nights with leg cramps present
2 weeks
9.5 days with magnesium 7.7 days with placebo Absolute results not reported
P = 0.27
Not significant
Systematic review
84 pregnant women Data from 1 RCT
Change in muscle spasms, 'absolute improvement' (complete resolution of cramping)
4 weeks
with magnesium with no treatment Absolute results not reported
Reported as no significant difference
P value not reported
The review reported there was no significant difference in 'relative improvement' (partial improvement) between groups (further details not reported)
Not significant
Systematic review
73 pregnant women Data from 1 RCT
Cramp intensity (0–100 mm VAS score)
from baseline to end of treatment
70.4 mm to 30.3 mm with magnesium 68.2 mm to 47.8 mm with placebo Absolute results not reported
P <0.05
Effect size not calculated
magnesium
Systematic review
45 pregnant women with rest cramps Data from 1 RCT
Mean cramp intensity score (scale where 0 = no pain to 4 = severe pain)
2 weeks
13.2 with magnesium 11.4 with placebo Absolute results not reported
The first RCT (73 women) had unclear randomisation and allocation concealment, and it was unclear how well the outcomes were predefined; the second RCT (45 women) had unclear allocation concealment; the third RCT (84 women) had unclear randomisation and allocation concealment, and had an unusual design where each treatment was given over 2 weeks but efficacy was assessed at 4 weeks. It was published as a 'brief communication' letter only. Only the second RCT used a cramp diary, the other two RCTs recalling cramp frequency at the time of the exit interview.
Comment
The review reported that it was unclear whether magnesium supplementation provided an advantage over placebo as the two relevant studies were discordant and did not report results in such a way as to allow the pooling of data. The two placebo-comparison studies were double-blind RCTs in Scandinavian maternity clinics and used the same intervention (a chewable tablet taken once each morning). The RCT (84 women) which compared magnesium with no treatment found no significant benefit. The review noted that for women suffering pregnancy associated muscle cramps the literature was conflicting and unclear, and further trials were needed.
Substantive changes
Magnesium salts for leg cramps in pregnancy One systematic review added. Categorisation changed from 'likely to be beneficial' to 'unknown effectiveness'.
BMJ Clin Evid. 2015 May 13;2015:1113.
Multivitamins and mineral supplements for leg cramps in pregnancy
We don’t know how multivitamin and mineral supplements compare with placebo at reducing leg cramps in pregnant women.
Benefits and harms
Multivitamin and mineral supplements versus placebo:
We found one systematic review (search date 2011), which identified one RCT. We have reported directly from the RCT.
Leg cramp symptoms
Multivitamin and mineral supplements compared with placebo We don’t know how multivitamin and mineral supplements compare with placebo at reducing leg cramps in pregnant women (very low-quality evidence).
Ref (type)
Population
Outcome, Interventions
Results and statistical analysis
Effect size
Favours
Leg cramp symptoms
RCT
62 pregnant women In review
Proportion of women reporting persistent leg cramps
ninth month of pregnancy
2/11 (18%) with multivitamin plus mineral tablet (containing 12 different ingredients) 10/18 (56%) with placebo
OR 0.23
95% CI 0.05 to 1.01
The RCT had a high dropout rate, and may be underpowered; see Further information on studies for full details
The RCT was primarily undertaken to examine the effects of a multivitamin plus mineral supplement on zinc and copper levels in maternal plasma during pregnancy. The supplement contained zinc gluconate, copper gluconate, iron gluconate, magnesium lactate, chromium chloride, ascorbic acid, thiamine nitrate, riboflavin (riboflavine), pyridoxal chlorhydrate, folic acid, cyanocobalamin, and alpha tocopherol acetate. Methodological limitations The RCT may have lacked power to detect a clinically important difference between treatment groups given that the confidence interval lies close to significance. In total, 29/62 (48%) women were assessed for cramp at 9 months’ gestation. The high withdrawal rate was not explained.
Comment
It is not possible to draw robust conclusions from this RCT given its methodological limitations.
Substantive changes
Multivitamins and mineral supplements for leg cramps in pregnancy One systematic review updated. Categorisation unchanged (unknown effectiveness).
We found no clinically important information from RCTs about sodium chloride in the treatment of leg cramps in pregnant women.
Benefits and harms
Sodium chloride versus placebo:
We found one systematic review (search date 2011), which identified no RCTs (see Comment).
Comment
The systematic review identified one controlled clinical trial, which was of poor quality. Initially, sodium chloride and calcium lactate were given to alternate participants. It was then decided, based on the difference between the results of the two treatments, to use two additional control groups (saccharin and no treatment). The dose of sodium chloride changed during the course of the study.
Substantive changes
Sodium chloride for leg cramps in pregnancy One systematic review updated. Categorisation unchanged (unknown effectiveness).
BMJ Clin Evid. 2015 May 13;2015:1113.
Vitamin B6 (pyridoxine) for leg cramps in pregnancy
We found no clinically important information from RCTs about vitamin E in the treatment of leg cramps in pregnant women.
Benefits and harms
Vitamin E versus placebo:
We found one systematic review (search date 2011), which identified no RCTs of vitamin E in pregnant women with leg cramps. We found no subsequent RCTs that met BMJ Clinical Evidence inclusion criteria.
Comment
We found one non-systematic review, which identified one trial, which we were unable to obtain through any of the sources available to us. Therefore, we were unable to assess it for possible inclusion in the review.
Substantive changes
Vitamin E for leg cramps in pregnancy One systematic review updated. Categorisation unchanged (unknown effectiveness).
