Treatment for cramps in amyotrophic lateral sclerosis/motor neuron disease

Abstract

Background

Cramps are painful, involuntary muscle contractions. They commonly affect people with amyotrophic lateral sclerosis/motor neuron disease (ALS/MND) at all stages of the disease. To date, the treatment of muscle cramps in ALS has been largely empirical without any evidence from randomised controlled trials.

Objectives

To systematically assess the effect of interventions on muscle cramps as a primary or secondary endpoint or adverse event in people with ALS/MND.

Search methods

We searched the Cochrane Neuromuscular Disease Group Specialized Register (14 February 2011), the Cochrane Central Register of Controlled Trials (Issue 1, 2011 in The Cochrane Library), MEDLINE (January 1966 to January 2011) and EMBASE (January 1980 to January 2011) and reference lists of articles searched using the terms motor neuron disease, motor neurone disease, motoneuron disease or amyotrophic lateral sclerosis. We contacted authors of trials for further information.

Selection criteria

We included all randomised and quasi‐randomised trials of oral medications in people with ALS which assessed cramps as a primary or secondary outcome measure or as an adverse event. We also included trials using subcutaneous or intravenous medications or physical therapy.

Data collection and analysis

All authors applied the selection criteria and assessed study quality independently, and all authors performed independent data extraction.

Main results

Twenty studies including 4789 participants were identified. Only one trial, of tetrahydrocannabinol (THC), assessed cramps as the primary endpoint. Thirteen studies assessed cramps as a secondary endpoint. The medications comprised vitamin E, baclofen, riluzole, L‐threonine, xaliproden, indinavir, and memantine. Six studies assessed cramps as an adverse event. The medications comprised creatine, gabapentin, dextromethorphan, quinidine, and lithium. In all 20 studies no favourable effect for the treatment of cramps in ALS/MND could be demonstrated, but many studies were underpowered to draw a definite conclusion. A meta‐analysis of two small studies showed a statistically nonsignificant result for the amino acid L‐threonine for the treatment of cramps in ALS/MND. No study was identified using physical therapy as a therapeutic intervention for cramps.

Authors' conclusions

There is no evidence to support the use of any intervention for muscle cramps in ALS/MND. More and larger randomised controlled trials evaluating treatments for muscle cramps in ALS/MND are needed.

Plain language summary

Treatment for cramps in amyotrophic lateral sclerosis/motor neuron disease

A cramp is a sudden, involuntary painful contraction of a muscle. Many people with amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND), experience cramps during the course of the disease. These range from mild cramps that do not affect daily activities and sleep, through to very severe, painful cramps. Some medications that are used to treat cramps in people with no medical condition or with conditions other than ALS have been tested in ALS clinical trials. These medicines include vitamin E, creatine, quinidine, and gabapentin. Other medications such as quinine sulfate, magnesium, lioresal, dantrolene, clonazepam, diphenylhydantoin, and gabapentin have been used to treat cramps in people with ALS but their effectiveness is unknown. In 2006 and 2010 the US Food and Drugs Administration issued warnings concerning the use of quinine sulfate, which was the previously most widely prescribed medication for cramps in the US. This review sought to find out how effective medications and physical treatments for cramps are for people with ALS. The reviewers identified 20 randomised controlled trials in people with ALS comprising a total of 4789 participants. Only one trial, of the drug tetrahydrocannabinol (THC), directly investigated the effectiveness of an intervention for cramps. Thirteen randomised controlled ALS trials investigated cramps secondarily among other variables. The medications comprised vitamin E, baclofen, riluzole, L‐threonine, xaliproden, indinavir, and memantine. Six randomised controlled ALS trials investigated cramps as adverse events. The medications comprised creatine, gabapentin, dextromethorphan, quinidine and lithium. None of the 20 studies could demonstrate any benefit, but the studies were small. Current evidence on the treatment of cramps in ALS is lacking and more research is needed.

Background

A cramp is a sudden, involuntary and painful muscle contraction, accompanied by palpable knotting of the muscle. The origin of cramps is incompletely understood and depends on the underlying condition (Kiernan 2001; Parisi 2000; Roeleveld 2000). Two different pathophysiological mechanisms have been proposed to cause cramps: abnormal excitation of the terminal branches of motor axons (Bertolasi 1993; Denny‐Brown 1953; Layzer 1994) and hyperexcitability or bistability of motoneurons at a spinal level (Baldissera 1994; Norris 1957; Ross 1995). Both mechanisms may complement each other (Parisi 2000). In amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND), cramps may result from impaired inhibitory mechanisms (for example impairment of interneurons mediated by GABA, the most abundant inhibitory neurotransmitter) (Obi 1993).

Many people with ALS/MND experience cramps during the course of the disease (Swash 2000). In a survey of symptom management in 84 people with ALS/MND, cramps were present in 62%, requiring treatment in 56% (Heiman‐Patterson 2000). Frequently, cramps occur as the first symptom of the disease, months before the patients notice weakness and wasting (Gubbay 1985; Layzer 1982). Severity varies from mild, without affecting daily activities and sleep, to disabling, where almost any voluntary muscle activity induces persistent, severely painful cramping. In ALS/MND, the cramps may affect any muscle or muscle group (for example jaw, abdomen, chest, back, neck, or extremities). Various medications such as quinine sulfate, magnesium, lioresal, dantrolene, clonazepam, diphenylhydantoin and gabapentin are used for the treatment of cramps in ALS/MND (Forshew 2003). However, treatment of cramps in ALS/MND has been a primary endpoint only in a single randomised controlled trial with tetrahydrocannabinol (THC) (Weber 2010) and an open‐label, nonrandomised study with levetiracetam (Bedlack 2009). Moreover, for quinine sulfate, the most widely prescribed medication for cramps in the US (Forshew 2003) the FDA has repeatedly issued safety announcements that it is only approved for the treatment of malaria and not approved for the treatment or prevention of night time leg cramps (FDA 2006; FDA 2010). However, off‐label use, for example in therapy‐refractory muscle cramps, is also discussed and prescribing physicians are advised to be alert to possible serious adverse events such as thrombocytopenia. Also, the American Academy of Neurology (AAN) practice parameter issued safety concerns about prescribing quinine for muscle cramps (Miller 2009). By contrast, a recent Cochrane review on quinine for 'idiopathic' muscle cramps found moderate quality evidence that quinine is effective and moderate quality evidence of significantly increased minor adverse events (mainly gastrointestinal symptoms), but no significantly increased serious adverse events (El‐Tawil 2010).

In populations other than people with ALS, numerous medications, including vitamins (Chan 1998; Connolly 1992; Khajehdehi 2001), gabapentin (Mueller 1997; Serrao 2000), quinine sulfate (Connolly 1992; Gorlich 1991; Fowler 1997; Fung 1989; Gorlich 1991; Jansen 1994; Jansen 1997; Lee 1991; Man‐Son‐Hing 1998), L‐carnitine (Ahmad 1990), prazosin (Sidhom 1994), and magnesium (Frusso 1999) have been investigated in controlled clinical trials evaluating the treatment of cramps. The conditions under investigation were haemodialysis (Ahmad 1990; Sidhom 1994), hypertension (Chan 1998), and disorders such as multiple sclerosis (Mueller 1997), cirrhosis (Lee 1991), and undefined diseases (Gorlich 1991; Fowler 1997; Serrao 2000). Other study populations included healthy people (Connolly 1992; Fung 1989; Jansen 1997; Jansen 1994; Lee 1991). A Cochrane review explored the interventions for leg cramps in pregnancy (Young 2002). Most of the studies showed a significant positive effect in favour of the treatment arm. Contradictory results have been found for magnesium (positive in pregnancy (Young 2002), negative in an undefined population (Frusso 1999)) and vitamin E (positive in hemodialysis (Khajehdehi 2001), negative in veterans (Connolly 1992)). Although the pathophysiology of cramps in these disorders and ALS/MND may differ (Obi 1993; Parisi 2000; Piergies 1990; Sidhom 1994), it is possible that some of the aforementioned compounds may be effective in ALS/MND. Among these compounds, vitamin E (Desnuelle 2001), gabapentin (Miller 2001; Miller 1996) and dextromethorphan/quinidine (Brooks 2004) have been investigated in randomised controlled clinical trials in people with ALS. None of them, including gabapentin (Miller 2001), seemed to alleviate cramps. All published trials used either the daily number of cramps and/or a visual analogue scale (VAS) reflecting the severity of cramps. However, the VAS for cramps has never been formally validated. Nevertheless, since self‐assessment of cramps was part of many controlled clinical trials in ALS, data on the effect of the study medication on cramps should be available.

Objectives

To systematically assess the effect of interventions on muscle cramps as a primary or secondary endpoint or adverse event in people with ALS/MND.

Methods

Criteria for considering studies for this review

Types of studies

We included only randomised and quasi‐randomised trials. We accepted all study designs.

Types of participants

We included studies with participants diagnosed with probable, probable laboratory supported, or definite ALS according to the original (Brooks 1994) or revised El Escorial criteria (Brooks 2000).

Types of interventions

We included studies which used oral, subcutaneous and intravenous medications or physical treatment which potentially relieve cramps in ALS/MND.

Types of outcome measures

Primary outcomes

The primary outcome measure was the reduction in the (patient's) global impression of muscle cramp burden over a period of time rated with a visual analogue scale (VAS). A VAS is a psychometric response scale used to measure subjective characteristics or attitudes about a particular symptom. As widely used in the assessment of pain, a VAS reflects a range of no symptom burden at all (i.e. 0 or 0%) to maximal imaginable symptom burden (i.e. a score of 10 or 100%). In this review, the muscle cramp burden reflects a summary of number, duration and intensity of muscle cramps over a period of time. This primary outcome measure was selected because it was most commonly used in the ALS studies.

Secondary outcomes

1. Cramp intensity in the 24 hours preceding assessment by VAS.

2. Number of cramps in the 24 hours preceding assessment.

3. In studies where cramps were assessed as adverse events: ratio of participants experiencing cramps to total number of participants.

4. In studies primarily designed to treat cramps: quality of life measure, for example Short Form 36 Health Survey (SF‐36).

5. In studies primarily designed to treat cramps: adverse effects.

In studies designed to study cramps as a primary outcome measure, quality of life measures and adverse effects are also assessed. 'Summary of findings' tables of the assessment of cramps using a VAS for each intervention have been included as additional tables.

Search methods for identification of studies

We searched the Cochrane Neuromuscular Disease Group Specialized Register (14 February 2011) using the following search terms 'amyotrophic lateral sclerosis' OR 'motor neuron disease' OR 'motor neuron disease'. We also searched the Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 1, 2011 in The Cochrane Library), MEDLINE (January 1966 to January 2011) and EMBASE (January 1980 to January 2011). We contacted pharmaceutical companies and corresponding authors of relevant unpublished or published randomised placebo controlled clinical trials in ALS/MND (included in the Cochrane Neuromuscular Disease Group Specialized Register) personally to retrieve additional data on cramps.

Search strategies for MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials (CENTRAL) are in Appendix 1; Appendix 2, and Appendix 3, respectively.

Data collection and analysis

All review authors screened abstracts for randomised controlled treatment trials in people with ALS/MND using the inclusion criteria stated above. If the inclusion criteria were met, we retrieved the full text article and screened it to determine whether muscle cramps were assessed. If the full text paper did not mention muscle cramps, we excluded the study. If muscle cramps were assessed as a primary or secondary outcome measure or as side effects, we included the study and contacted all corresponding authors by email, and some personally. All review authors independently performed the extraction of data relating to the primary and secondary outcome measures and rated the risk of bias in the included studies. We resolved disagreement by discussion.

Assessment of risk of bias took into account the randomisation method, allocation concealment, participant and observer blinding, reporting of incomplete data, selective reporting, and risk of other bias. We followed the grading scale proposed in the Cochrane Handbook for Systematic Reviews of Interventions 5.1.0 (Table 8.5.c: Criteria for judging risk of bias in the ‘Risk of bias’ assessment tool (Higgins 2011) and graded each criterion as fulfilled ("Low risk"), not fulfilled ("High risk") or providing insufficient information to permit a "High risk" or "Low risk" judgement ("Unclear"). Figure 1 provides a summary of the review authors' judgements about each risk of bias for the included studies.

1.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

We used the mean difference and 95% confidence intervals (CI) for continuous outcome measures (for example absolute change in VAS). We assessed categorical outcome measures (for example the ratio of participants experiencing cramps versus not experiencing cramps) using risk ratios (RR) and 95% CI. We planned to use a fixed‐effect analysis unless we found evidence of heterogeneity.

Results

Description of studies

The current search strategy (14 February 2011) identified 729 abstracts in MEDLINE, 796 abstracts in EMBASE, 257 abstracts in the Cochrane Neuromuscular Disease Group Specialized Register, and 455 abstracts in CENTRAL, adding up to a total of 2237 abstracts. After deduplication, the authors reviewed 1461 abstracts. Amongst them, we classified 1284 as not relevant to the review, leaving 177 abstracts of interest. We were unable to retrieve the full text of 13 articles (listed in Table 1). Among the 164 full text articles retrieved, the review authors identified 19 relevant articles with a total of 20 trials that met the selection criteria (Meininger 2004 comprises two studies). We excluded 158 studies (including one additional, unpublished study by Gelinas 2001 (personal communication), as well as the aforementioned 13 studies in Table 1) because they did not meet the inclusion criteria. See Characteristics of excluded studies for the full list of excluded studies. In only one instance (De Carvalho 2010) did the study authors provide original data. The 20 included trials comprised a total of 4789 participants. The studies are summarised in the Characteristics of included studies and an ongoing trial is summarised in Characteristics of ongoing studies.

1. Full text articles not retrieved.

Study

Markland 1997

Mazzini 1994

Mazzini 1998

Meininger 1995

Nagano 2005

Poutiainen 1994

Strevic 1998

Szczudlik 1998

Tyler 1978

Yanagisawa 1997

Zhang 2007

Thirteen studies assessed muscle cramps on a VAS once every study visit. Thus, the whole time since the last study visit was reflected in a single rating. None of the studies reported additional assessments of muscle cramps (for example by a daily or weekly log) or whether cramp number or duration of cramps were assessed. None of them specified whether the assessment by VAS reflected a global impression of cramp burden or, for instance, cramp intensity. All of them assessed muscle cramps as a secondary outcome. The review authors identified only two studies that assessed muscle cramps as a primary outcome (Weber 2010; Strong ongoing). Both assessed cramp intensity and cramp number (Strong ongoing also duration) with a daily journal covering the last 24 hours. All other studies investigated medications that aimed to modify the course of the disease or to treat emotional lability (Brooks 2004). Cramps were either assessed as secondary outcome measures, side effects or as part of the study protocol.

All studies except two (Brooks 2004; Chiò 2010) were RCTs comparing oral medication to placebo. Brooks 2004 compared quinidine to dextromethorphan and a combination of the two substances, Chiò 2010 compared therapeutic lithium serum levels to subtherapeutic levels. None of the studies used subcutaneous or intravenous applications and none of the studies used physical therapy as the therapeutic intervention.

One study was performed over 30 years ago (Norris 1979), one over 20 years ago (Blin 1989), nine more than 10 years ago and nine within the last 10 years. All studies examined outpatients. Five studies were carried out in the US, 15 in western Europe. One study (Bensimon 2002) explicitly studied people with ALS aged 75 years and older, all other studies included a wide range of ages (ranging from 20 to 75 years).

Study size varied considerably, ranging from very small (n = 12) to large scale (n = 959) trials. Five studies had 23 or fewer participants (Blin 1989; Blin 1992; Gil 1992; Norris 1979; Weber 2010); Scelsa 2005 had 46 participants and De Carvalho 2010 63. All other studies had 107 or more participants. Three of the five small‐scale (n = 23 or less) studies used a cross‐over design (Blin 1989; Gil 1992; Weber 2010), and two of them a parallel group design (Norris 1979; Blin 1992). All other studies used a parallel group design. The washout periods in the cross‐over trials (Blin 1989; Gil 1992; Weber 2010) were 7, 8 and 14 days, respectively.

Five studies were short term with an observational period of eight weeks or less. Fifteen studies were long term with an observational period of six months or more. Consequently, (cramp) assessment interval varied from once every week in the short‐term studies to once in six months in the long‐term trials. Assessment intervals are given for each study in Characteristics of included studies.

Eight studies applied interventions that were used in multiple trials: three trials (Bensimon 1994; Bensimon 2002; Lacomblez 1996) studied riluzole 100 mg per day, one trial Lacomblez 1996 studied 50 mg and 200 mg riluzole per day, three trials (Blin 1989; Blin 1992; Gil 1992) used L‐threonine (all 2 g per day), two trials (Meininger 2004, published as one study) investigated xaliproden. Five trials (Desnuelle 2001; Miller 2001; Norris 1979; Weber 2010; De Carvalho 2010) used medications not used in other trials (vitamin E, gabapentin, baclofen, THC, and lithium).

Risk of bias in included studies

The review authors graded each individual quality criterion for each study as set out in the methods section and tabulated individual scores (Characteristics of included studies). The quality of the trials varied considerably. Newer trials and trials conducted by professional pharmaceutical investigators were of better design, incorporating more appropriate statistical analysis, applying intention‐to‐treat analysis and taking into consideration baseline differences.

Effects of interventions

Primary outcome measure (reduction of impression of cramp burden over time rated by VAS)

The interventions comprised vitamin E, baclofen, riluzole, L‐threonine, xaliproden, indinavir, memantine, and THC. All 14 studies reported statistically nonsignificant differences between the intervention and control groups. One ongoing study identified by personal communication is assessing the effect of vitamin E on muscle cramps as a primary outcome measure (Strong ongoing).

A meta‐analysis could be performed for L‐threonine (Blin 1992;Gil 1992). The combined mean change of the cramp intensity was ‐12.61 on a VAS (95% CI ‐ 26.94 to 1.72) and the difference was statistically nonsignificant (P = 0.08) (see Figure 2). Data for the interventions vitamin E and THC were also reported allowing reanalysis (Desnuelle 2001; Weber 2010) (see Analysis 2.1 and Analysis 3.1, respectively). One author (De Carvalho 2010) provided unpublished data about memantine (Analysis 4.1).

2.

Forest plot of comparison: 6 L‐threonine, outcome: 6.1 Muscle cramp VAS.

2.1. Analysis.

Comparison 2 Vitamin E 1g/d versus placebo, Outcome 1 Muscle cramp VAS.

3.1. Analysis.

Comparison 3 Tetrahydrocannabinol (THC) versus placebo, Outcome 1 Muscle cramp VAS.

4.1. Analysis.

Comparison 4 Memantine versus placebo, Outcome 1 Muscle cramp VAS.

Secondary outcome measures (intensity of cramps by VAS in the last 24 hours, number of cramps in the last 24 hours, cramps as adverse events)

One study assessed intensity of cramps by VAS in the last 24 hours and number of cramps in the last 24 hours (Weber 2010) and a statistically nonsignificant difference was found.

All six studies assessing cramps as adverse events (Brooks 2004; Chiò 2010; Groeneveld 2003; Miller 1996; Rosenfeld 2008; Scelsa 2005) reported statistically nonsignificant differences. Only Rosenfeld 2008 (Analysis 4.1) and Scelsa 2005 (Analysis 6.1) reported the data (as a proportion of participants experiencing cramps). The interventions comprised dextromethorphan/quinidine, lithium, creatine, gabapentin, and indinavir.

6.1. Analysis.

Comparison 6 Indinavir versus placebo, Outcome 1 Cramps (side effect).

Discussion

The aim of this review was to assess the evidence for the treatment of cramps in ALS/MND. So far there is a lack of interventional studies targeted at treating cramps in ALS/MND. Treatment of cramps in ALS has been the primary endpoint in only one completed (Weber 2010) and one ongoing (Strong ongoing) RCT. The former trial, investigating the drug THC, did not find any treatment benefit (see Table 2). Thus, we also included studies assessing cramps as secondary outcome measures, as side effects (for example Scelsa 2005, see Table 3) or simply as part of the study protocol without specification as a primary or secondary outcome measure. Most of the identified studies were large‐scale ALS/MND trials investigating disease‐modifying interventions without any indication about the usefulness of the intervention for the treatment of muscle cramps in people with ALS/MND. It is therefore not surprising that all included studies that assessed muscle cramps found statistically nonsignificant differences between the intervention and control group.

2. Summary of findings: tetrahydrocannabinol (THC) (10 mg/d) for cramps in ALS/MND.

Tetrahydrocannabinol (10 mg/d) for cramps in ALS/MND (Weber 2010)
Patient or population: people with cramps in ALS/MND Settings: outpatients in Switzerland Intervention: tetrahydrocannabinol (10 mg/d)
Outcomes	Illustrative comparative risks (95% CI)		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Control	THC (10 mg/d)
Muscle cramps Severity of muscle cramps in last 24 hours on visual analogue scale (VAS) Follow‐up: 4 weeks	The mean muscle cramps in the control groups was 3.49 VAS (0‐10)	The mean muscle cramps in the intervention groups was 0.24 higher (0.32 to 0.81 higher)		44 (1 study, Weber 2010)	⊕⊕⊕⊕ high	The authors discuss a potential carry‐over effect which may have masked treatment effects
*The basis for the assumed risk is the control group mean. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). ALS/MND: amyotrophic lateral sclerosis/motor neuron disease; CI: confidence interval
GRADE Working Group grades of evidence High quality: further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: 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: we are very uncertain about the estimate.

3. Summary of findings: indinavir (2400 mg/d) for cramps in ALS/MND.

Indinavir (2400 mg/d), cramps as an adverse event in ALS/MND (Scelsa 2005)
Patient or population: people with cramps in ALS/MND Settings: outpatients in the USA Intervention: indinavir (2400 mg/d)
Outcomes	Illustrative comparative risks (95% CI)		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Control	Indinavir (2400 mg/d)
Muscle cramps Number of participants reporting muscle cramps as side effect during the observation period Follow‐up: 9 months	43 per 1000	87 per 1000 (8 to 893)	RR 2 (0.19 to 20.55)	46 (1 study, Scelsa 2005)	⊕⊕⊕⊝ moderate1
*The basis for the assumed risk is the control group mean. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; RR: risk ratio; ALS/MND: amyotrophic lateral sclerosis/motor neuron disease
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: 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: We are very uncertain about the estimate.

¹Study underpowered to detect an effect.

However, some trials were identified in this review that used medications in ALS/MND as disease‐modifying treatment which have also been used in non‐ALS populations for the treatment of cramps. They include vitamin E, creatine, gabapentin, dextromethorphan and quinidine. Data from the gabapentin trial and dextromethorphan/quinidine trial were not available.

The analysis of single trial data suggests that vitamin E and creatine, which have shown to be effective in other conditions (Khajehdehi 2001), do not affect cramps in people with ALS/MND (see Table 4 and Table 5). However, these studies were not powered for treatment effects on cramps so no conclusions can be drawn with respect to their effectiveness. This points to another fundamental problem of cramp trials in ALS/MND, which is that no formal studies exist about the natural course (for example prevalence, duration, frequency, and intensity).

4. Summary of findings: vitamin E (1 g/d) for cramps in ALS/MND.

Vitamin E (1 g/d) for ALS/MND (Desnuelle 2001)
Patient or population: people with ALS/MND Settings: outpatients in France Intervention: vitamin E (1 g/d)
Outcomes	Illustrative comparative risks (95% CI)		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Control	Vitamin E (1 g/d)
Muscle cramps Visual analogue scale (VAS) of global impression of cramps Follow‐up: 12 months	The mean muscle cramps in the control groups was 30.4 VAS (0‐100)	The mean muscle cramps in the intervention groups was 3.7 higher (2.01 lower to 9.41 higher)		288 (1 study, Desnuelle 2001)	⊕⊕⊕⊝ moderate1
*The basis for the assumed risk is the control group mean. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; ALS/MND: amyotrophic lateral sclerosis/motor neuron disease
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: 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: We are very uncertain about the estimate.

¹Risk of selective outcome reporting was judged as high (see 'Risk of bias' table).

5. Summary of findings: creatine monohydrate (5 g/d) for cramps in ALS/MND.

Creatine monohydrate (5 g/d) for cramps in ALS/MND (Rosenfeld 2008)
Patient or population: people with cramps in ALS/MND Settings: outpatients in the USA Intervention: creatine monohydrate (5 g/d)
Outcomes	Illustrative comparative risks (95% CI)		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Control	Creatine monohydrate (5 g/d)
Muscle cramps Number of participants reporting muscle cramps as side effect during the observation period Follow‐up: 9 months	241 per 1000	132 per 1000 (58 to 306)	RR 0.55 (0.24 to 1.27)	107 (1 study, Rosenfeld 2008)	⊕⊕⊕⊕ high
*The basis for the assumed risk is the control group mean. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; RR: risk ratio; ALS/MND: amyotrophic lateral sclerosis/motor neuron disease
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: 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: We are very uncertain about the estimate.

One of the inherent difficulties was the assessment of the symptom of interest itself, that is muscle cramps. Total muscle cramp burden can be subdivided into number, duration and intensity (or severity, the two terms were used interchangeably in this review) of muscle cramps. As muscle cramps are in most part constituted by pain, a patient has to rate this solely subjective symptom on a scale between zero and maximal symptom burden. As in pain, this was assessed with a VAS. Of the large scale, high quality ALS/MND intervention trials, all assessed muscle cramps by VAS only at every study visit. Since no indication was given that muscle cramps were assessed at a higher frequency outside the visits (for example with a daily log), the assessments probably reflect a global impression of cramp burden over the weeks to months since the previous visit, which implements a high recall bias. To reach a more firm conclusion, future intervention trials need to assess cramp number, duration and intensity on a daily basis.

Another difficulty was that data on muscle cramps were not reported. Of the 20 trials assessing cramps, only five reported the data. Unpublished data could be retrieved only from one trial (De Carvalho 2010) (see Table 6). The latter and the published data were re‐analysed in this review. Only two trials (Blin 1992; Gil 1992) reported on the same intervention (L‐threonine) and a meta‐analysis resulted in a statistically nonsignificant difference (see Table 7). In no other instance were data on cramps reported twice or more and thus we were not able to pool the data.

6. Summary of findings: memantine (20 mg/d) for cramps in ALS/MND.

Memantine (20 mg/d) for cramps in ALS/MND (De Carvalho 2010)
Patient or population: people with ALS/MND Settings: outpatients in Portugal Intervention: memantine (20 mg/d)
Outcomes	Illustrative comparative risks (95% CI)		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Control	Memantine (20 mg/d)
Muscle cramps Visual analogue scale (VAS) of global impression of cramps Follow‐up: 12 months	241 per 1000	207 per 1000 (80 to 540)	RR 0.86 (0.33 to 2.24)	58 (1 study, De Carvalho 2010)	⊕⊕⊕⊕ high
*The basis for the assumed risk is the control group mean. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; RR: risk ratio; ALS/MND: amyotrophic lateral sclerosis/motor neuron disease
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: 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: We are very uncertain about the estimate.

7. Summary of findings: L‐threonine (2 g/d) for cramps in ALS/MND.

L‐threonine (2 g/d) for ALS/MND (Blin 1989; Gil 1992)
Patient or population: people with ALS/MND Settings: outpatients in France Intervention: L‐threonine (2 g/d)
Outcomes	Illustrative comparative risks* (95% CI)		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Control	L‐threonine (2 g/d)
Muscle cramps Visual analogue scale (VAS) of global impression of cramps since last study visit (varied) Follow‐up: 2 to 12 weeks	The mean muscle cramps in the control groups was 29.63 VAS (0‐100)1	The mean muscle cramps in the intervention groups was 12.61 lower (26.94 lower to 1.72 higher)		55 (2 studies, Blin 1989 and Gil 1992)	⊕⊝⊝⊝ very low2,3
*The basis for the assumed risk is the control group mean. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; ALS/MND: amyotrophic lateral sclerosis/motor neuron disease
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: 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: We are very uncertain about the estimate.

¹The mean is the weighted average of the two control groups. 
 ²One study (Gil 1992) used quasi‐randomised allocation of the cross‐over sequence (see 'Risk of bias' table). 
 ³ Very small sample sizes.

Authors' conclusions

Implications for practice.

Based on results of this review, there is no evidence to support the use of any intervention for muscle cramps in people with ALS/MND.

Implications for research.

More trials aimed to investigate the treatment of cramps in ALS/MND are needed. Studies directly addressing muscle cramps in ALS should assess number and duration of muscle cramps as well as intensity of muscle cramps on a VAS.

History

Protocol first published: Issue 2, 2003
 Review first published: Issue 4, 2012

Date	Event	Description
2 September 2008	Amended	Converted to new review format.

Appendices

Appendix 1. MEDLINE search strategy

1 randomised controlled trial.pt. 
 2 controlled clinical trial.pt. 
 3 randomized.ab. 
 4 placebo.ab. 
 5 clinical trials as topic.sh. 
 6 randomly.ab. 
 7 trial.ti. 
 8 or/1‐7 
 9 (animals not (animals and humans)).sh. 
 10 8 not 9 
 11 exp Motor Neuron Disease/ 
 12 (moto$1 neuron$1 disease$1 or moto?neuron$1 disease).mp. 
 13 ((Charcot marie$1 adj5 syndrome$1) or (Lou Gehrig$1 adj5 syndrome$1)).mp. 
 14 ((Charcot marie$1 adj5 disease) or (Lou Gehrig$1 adj5 disease)).mp. 
 15 Amyotrophic Lateral Sclerosis.mp. 
 16 or/11‐15 
 17 10 and 16

Appendix 2. EMBASE search strategy

1 crossover‐procedure/ 
 2 double‐blind procedure/ 
 3 randomised controlled trial/ 
 4 single‐blind procedure/ 
 5 (random$ or factorial$ or crossover$ or cross over$ or cross‐over$ or placebo$ or (doubl$ adj blind$) or (singl$ adj blind$) or assign$ or allocat$ or volunteer$).tw. 
 6 or/1‐5 
 7 human/ 
 8 6 and 7 
 9 human/ or nonhuman/ 
 10 6 not 9 
 11 8 or 10 
 12 exp Motor Neuron Disease/ 
 13 (moto$1 neuron$1 disease$1 or moto?neuron$1 disease).mp. 
 14 ((Charcot marie$1 adj5 syndrome$1) or (Lou Gehrig$1 adj5 syndrome$1)).mp. 
 15 ((Charcot marie$1 adj5 disease) or (Lou Gehrig$1 adj5 disease)).mp. 
 16 Amyotrophic Lateral Sclerosis.mp. 
 17 or/12‐16 
 18 11 and 17

Appendix 3. Cochrane Central Register of Controlled Trials (CENTRAL)

#1MeSH descriptor Motor Neuron Disease explode all trees 
 #2(amyotrophic NEXT lateral NEXT sclerosis) OR (motor NEXT neuron* NEXT disease*) OR (motoneuron* NEXT disease*) 
 #3(lou NEXT Gehrig*) 
 #4(#1 OR #2 OR #3)

Data and analyses

Comparison 1. L‐threonine 2 g/d versus placebo.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Muscle cramp VAS	2	55	Mean Difference (IV, Fixed, 95% CI)	‐12.61 [‐26.94, 1.72]

1.1. Analysis.

Comparison 1 L‐threonine 2 g/d versus placebo, Outcome 1 Muscle cramp VAS.

Comparison 2. Vitamin E 1g/d versus placebo.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Muscle cramp VAS	1	288	Mean Difference (IV, Fixed, 95% CI)	3.70 [‐2.01, 9.41]

Comparison 3. Tetrahydrocannabinol (THC) versus placebo.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Muscle cramp VAS	1		Mean Difference (Fixed, 95% CI)	0.24 [‐0.31, 0.79]

Comparison 4. Memantine versus placebo.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Muscle cramp VAS	1	58	Risk Ratio (M‐H, Fixed, 95% CI)	0.86 [0.33, 2.24]

Comparison 5. Creatine versus placebo.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Cramps (side effect)	1	107	Risk Ratio (M‐H, Fixed, 95% CI)	0.55 [0.24, 1.27]

5.1. Analysis.

Comparison 5 Creatine versus placebo, Outcome 1 Cramps (side effect).

Comparison 6. Indinavir versus placebo.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Cramps (side effect)	1	46	Risk Ratio (M‐H, Fixed, 95% CI)	2.0 [0.19, 20.55]

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Bensimon 1994.

Methods	Double‐blind, randomised, placebo‐controlled parallel trial Assessment of cramps (patient's global impression of muscle cramp burden over the time between study visits as rated by VAS) at week 0, 8,16, 24, 32, 40, 48
Participants	155 participants (64 female, 91 male), aged 20 to 75 years with probable or definite ALS
Interventions	Riluzole 100 mg/day Placebo Identical‐appearing tablets taken twice daily
Outcomes	Primary outcome: death or tracheostomy after 12 months Secondary outcomes: among others, cramps expressed on 100 mm VAS. Cramps assessment was not statistically different among the 2 groups, data were not reported
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: " ...We conducted a prospective, randomised, double‐blind, placebo‐controlled, stratified trial... Randomisation was stratified according to the centre where the patient was treated (one of seven centres) and the site of the onset of disease (a limb or the bulbar region)..."Comment: the specific randomisation method is not reported, but randomisation was done centrally. Sequence generation probably adequate
Allocation concealment (selection bias)	Low risk	Quote: "treatment assignments were made separately in each centre and were based on randomisation codes established by blocking"
Blinding (performance bias and detection bias) All outcomes	Low risk	Quote: "We conducted a...double‐blind...trial...Treatment assignments...were based on randomisation codes...". Furthermore, 24 patients who did not entirely meet the inclusion criteria...were only after unblinding found to be evenly distributed among the groups
Incomplete outcome data (attrition bias) All outcomes	Low risk	Quote: "Overall, 44 patients discontinued treatment during the study (27 in the riluzole group and 17 in the placebo group). Among the 27 patients in the riluzole group, 19 (70%) discontinued treatment because of adverse effects, as compared to 9 of the 15 patients (60%) in the placebo group." Adverse effects comprised increase of asthenia, spasticity, increase in liver enzymes, and elevation in blood pressure
Selective reporting (reporting bias)	High risk	Incomplete reporting of secondary outcome measures
Other bias	Low risk	Comment: no other bias was observed

Bensimon 2002.

Methods	Double‐blind, randomised, placebo‐controlled parallel trial Assessment of cramps (patient's global impression of muscle cramp burden over the time between study visits as rated by VAS) at week 0, 24, 48, 72
Participants	168 participants (86 female, 82 male) with probable or definite ALS comprising one of three inclusion criteria: age over 75 years; or disease duration over 5 years since first symptoms; or forced vital ventilatory capacity below 60% of the theoretical maximum value or not assessable
Interventions	Riluzole 100 mg/day Placebo Tablets taken twice daily
Outcomes	Primary outcome: death or tracheostomy after 18 months Secondary outcomes: cramps expressed on a 100 mm VAS. Cramps were not significantly different among the two groups, data were not reported
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Patients were randomly assigned to one of the two treatment groups...according to a randomisation list balanced by centre...No information on the previously allocated double‐blind treatment was given to the investigator or to the patient"
Allocation concealment (selection bias)	Low risk	Comment: randomisation was done centrally
Blinding (performance bias and detection bias) All outcomes	Low risk	Quote: "...No information on the previously allocated double‐blind treatment was given to the investigator or to the patient..."
Incomplete outcome data (attrition bias) All outcomes	Low risk	Comment: reasons for an early study termination were adequately specified in both groups. 35 participants discontinued treatment before the end of the study. Among the 22 withdrawals in the riluzole group, 15 (68%) were due to adverse effects, as compared to 8 of the 13 withdrawals (62%) in the placebo group. Adverse effects comprised impaired respiratory function or liver enzyme elevations
Selective reporting (reporting bias)	Low risk	Although the results of the secondary outcome measures were not reported, it was stated that all of them were not statistically different between the 2 groups
Other bias	Low risk	Comment: no other bias was observed

Blin 1989.

Methods	Double‐blind, randomised, placebo‐controlled cross‐over trial Assessment of cramps (patient's global impression of muscle cramp burden over the time between study visits as rated by VAS) at week 0, 1, 3
Participants	12 participants (gender not reported) with probable or definite ALS
Interventions	L‐Threonine 2 g/day for 7 days Placebo for 7 days One capsule once daily with a washout period of 7 days
Outcomes	Outcome measures (primary outcome measure not stated): manual muscle strength, hand grip dynamometry, Tufts bulbar score and...cramps expressed on a 100 mm VAS. Cramps assessment was not significantly different among the 2 groups, data were not reported
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "Le plan experimental etait un essai randomise en cross over, en double aveugle contre placebo ... " Translation: "The study was planned as a randomised placebo‐controlled cross‐over trial ..." Comment: insufficient information to permit judgement of ‘Yes’ or ‘No’.
Allocation concealment (selection bias)	Unclear risk	Quote: "Le plan experimental etait un essai randomise en cross over, en double aveugle contre placebo ... " Translation: "The study was planned as a randomised placebo‐controlled cross‐over trial ..." Comment: insufficient information to permit judgement of ‘Yes’ or ‘No’
Blinding (performance bias and detection bias) All outcomes	Low risk	Quote: "... Des gelules indiscernables de placebo (lactose) ou L‐threonine (2 g/j) ..." Translation: "Indistinguishable capsules of placebo (lactose) or L‐threonine (2 g/d) were administered."
Incomplete outcome data (attrition bias) All outcomes	High risk	Comment: no information concerning incomplete outcome data was provided
Selective reporting (reporting bias)	Low risk	The results of the secondary outcome measures were not reported. It was stated that all secondary outcomes not reported (reported were measurements of muscle strength using the MRC scale and hand grip dynamometry) were statistically not significantly different between the 2 groups
Other bias	Low risk	Comment: no other bias was observed

Blin 1992.

Methods	Double‐blind, randomised, placebo‐controlled parallel trial Assessment of cramps (patient's global impression of muscle cramp burden over the time between study visits as rated by VAS) at week 0,12, 24, 36, 48
Participants	23 participants (10 female, 13 male) with probable or definite ALS
Interventions	L‐threonine 2 g/day Placebo Powder taken orally once daily
Outcomes	Outcome measures (primary outcome measure not stated): manual muscle strength, hand grip dynamometry, and ... cramps expressed on a 100‐mm VAS. Cramps assessment was not significantly different among the two groups, data were not reported
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "...patients were...randomised..."
Allocation concealment (selection bias)	Unclear risk	Quote: "...patients were entered sequentially..." Comment: insufficient information to permit judgement of ‘Yes’ or ‘No’
Blinding (performance bias and detection bias) All outcomes	Low risk	Quote: "...double blind....lactose powder as placebo..."
Incomplete outcome data (attrition bias) All outcomes	High risk	Quote: "...15 of 23 patients completed..." Comment: reasons given only for 2 of the 8 participants
Selective reporting (reporting bias)	Unclear risk	Insufficient information to permit judgement of ‘Low risk’ or ‘High risk’
Other bias	Low risk	Comment: no other bias was observed

Brooks 2004.

Methods	Double‐blind, randomised, parallel trial Assessment of cramps (as adverse effects) at week 0, 2, 4
Participants	129 participants (49 female, 80 male) with probable or definite ALS
Interventions	Quinidine (Q) 60 mg/d Dextromethorphan (D) 60 mg/d Q + D (60 mg/d each)
Outcomes	Primary outcome: change in a pseudobulbar affect score Secondary outcomes: number of laughing or crying episodes per week, quality of life and quality of relationship scores Cramps were assessed as adverse effects. Adverse effects were not significantly different between the groups
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "The study was randomised by centre. Randomisation was blocked to ensure approximately equal representation within treatment centres using a computer algorithm."
Allocation concealment (selection bias)	Low risk	Study drug was randomised by Sharp Clinicals (Conshohocken, PA) and shipped directly to the clinical study sites. The sponsor and investigators were blinded to treatment allocation. Investigators were shipped Q + D, D, and Q in identical blister‐pack cards that were dispensed in strict sequence.
Blinding (performance bias and detection bias) All outcomes	Low risk	All were identical in appearance. The sponsor and investigators were blinded to treatment allocation. Investigators were shipped Q + D, D, and Q in identical blister‐pack cards that were dispensed in strict sequence.
Incomplete outcome data (attrition bias) All outcomes	High risk	Insufficient reporting of missing outcome data of participants who discontinued the study due to adverse events to permit judgement of ‘Yes’ or ‘No’
Selective reporting (reporting bias)	Low risk	NCT00021697. Primary and secondary outcome measures were not stated. The results of all outcome measures were reported.
Other bias	Low risk	Comment: no other bias was observed

Chiò 2010.

Methods	Single‐blind, randomised, controlled parallel dose‐finding trial Cramps were not assessed prospectively. Study visits were at week 12, 24, 36, 48, and 60.
Participants	171 participants (71 female, 100 male) with probable or definite ALS, all taking 50mg riluzole twice daily
Interventions	Group 1 was targeted at a therapeutic lithium serum level Group 2 was targeted at a subtherapeutic lithium serum level
Outcomes	The composite primary outcome measure was survival or severe loss of autonomy, defined as the time from inclusion to death/tracheostomy or at least 2 of the following ALSFRS‐R scores: 1 for swallowing, 1 for walking, or 2 for respiratory insufficiency Secondary endpoints were the mean monthly variation of 1) the ALSFRS‐R total score and 2) the FVC% value; 3) the number of therapeutic failures (treatment stops for ineffectiveness, adverse events, or both); and 4) quality of life score Cramps were assessed as adverse effects, number of participants was not given
Notes	117 participants (68%) discontinued due to adverse effects and the trial was stopped prematurely. The vast majority of adverse effects were attributed to the lithium therapy and comprised tremor, thyroid disturbances including thyroiditis, polyuria, deep venous thrombosis, gastrointestinal disturbances, cardiac disturbances (1 fatal and 1 non‐fatal arrhythmia, 1 myocardial infarction), muscle pain, and severe cramps (number of participants not given)
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Randomization was performed separately for each centre, according to predetermined lists. Patients were stratified according to FVC% at enrolment (50%–79% vs 80%)."
Allocation concealment (selection bias)	Low risk	Quote: "Randomization was performed separately for each centre, according to predetermined lists. Patients were stratified according to FVC% at enrolment (50%–79% vs 80%)."
Blinding (performance bias and detection bias) All outcomes	Low risk	Quote: "To preserve blindness, each patient was followed by 2 physicians: a treating physician, who was aware of the treatment allocation, adjusted the dose of the drug in order to keep the target blood level of lithium, and watched for adverse events; and an evaluating physician, who was not aware of treatment allocation and performed all clinical assessments."
Incomplete outcome data (attrition bias) All outcomes	High risk	Comment: although the incomplete data was adequately reported there remains a high risk for attrition bias
Selective reporting (reporting bias)	Low risk	The results of all outcome measures were reported
Other bias	Low risk	Comment: no other bias was observed

De Carvalho 2010.

Methods	Double‐blind, randomised, placebo‐controlled parallel trial Assessment of cramps (patient's global impression of muscle cramp burden over the time between study visits as rated by VAS) at week 12, 24, 36, and 48
Participants	63 participants (21 female, 42 male) with probable or definite ALS, all taking 50mg riluzole twice daily
Interventions	Memantine 10 mg twice daily Placebo
Outcomes	The primary outcome was change in the ALSFRS (40‐point rating scale) from baseline to 12 months Secondary outcomes were: predicted value of FVC; manual muscle testing (32 muscle groups as classified on the MRC scale, maximal score 160); patient 100 mm VAS (for fasciculations, cramps, fatigue and stiffness); medical 100 mm VAS (global: worse, stable, improved); quality of life (SF‐36); motor unit number estimation of both ADM (incremental technique); and neurophysiological index (NI) of both ADM. For the neurophysiological measurements the mean value from both hands was calculated and its value used in the analysis Quote: "There was no significant difference between memantine and placebo groups."
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Randomization was independently performed by the clinical research unit of our department, although a computer‐generated list and randomisation codes were kept blinded to the study investigators and statisticians." Stratification by region of onset (limb vs bulbar) within each treatment arm was undertaken, and a block of 4 was used in each stratum. Participants were assigned (ratio of 1:1) to placebo or memantine
Allocation concealment (selection bias)	Low risk	Quote: "Masked study medication was supplied for dispensation in blister packs at each visit. Drug and placebo tablets were visually identical."
Blinding (performance bias and detection bias) All outcomes	Low risk	As quoted above
Incomplete outcome data (attrition bias) All outcomes	Low risk	Comment: adequate reporting of incomplete data
Selective reporting (reporting bias)	Low risk	Protocol including primary and secondary (all but evaluation of fasciculations, cramps, stiffness and fatigue) outcome measures were published (NCT00353665). The results of all outcome measures were reported except evaluation of fasciculations, cramps, stiffness and fatigue, but a statement was made that none of them were statistically significantly different among the two groups. Summarized cramp results were provided by personal communication
Other bias	Low risk	Comment: no other bias was observed

Desnuelle 2001.

Methods	Double‐blind, randomised, placebo‐controlled parallel trial Assessment of cramps (patient's global impression of muscle cramp burden over the time between study visits as rated by VAS) at week 0,12, 24, 36, 48
Participants	289 participants (130 female, 158 male) with probable or definite ALS
Interventions	Vitamin E 1000 mg/day + riluzole 100 mg/day Placebo + riluzole 100 mg/day two identically appearing capsules (vitamin E versus placebo) twice daily and Riluzole tablets twice daily
Outcomes	Primary outcome: change in functional status of each participant using the modified Norris limb scale Secondary outcomes: survival (the time to death or tracheostomy), bulbar function assessed with the Norris bulbar scale and manual muscle testing. Fatigue, limb stiffness, cramps and fasciculations were assessed with VAS Cramps were not significantly different among the two groups, data were not reported
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "...The randomisation was balanced by centre... "
Allocation concealment (selection bias)	Low risk	Quote: "...Patients were randomly assigned to one of the two treatment groups according to a randomisation schedule... "
Blinding (performance bias and detection bias) All outcomes	Low risk	Quote: "...This study was designed as a double blind, placebo‐controlled randomised clinical trial... placebo (identically‐appearing capsules b.i.d.)..."
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Quote: "One hundred and forty‐six patients (74 in the placebo group and 72 in the a ‐tocopherol group) did not complete the 12‐month treatment period. Of these, 69 died or underwent a tracheostomy during the study period. Of the patients who discontinued treatment before the end of the study for reasons other than death, the principal reasons were withdrawal of consent or the occurrence of adverse events. The number of treatment discriminations, and the reasons for these, were equally balanced between the two groups." Comment: adequate reporting of incomplete data
Selective reporting (reporting bias)	High risk	Although referring to 2 previous studies concerning protocol and primary and secondary outcome measures, not survival but a change in the Norris limb scale (which was a secondary outcome measure in the aforementioned 2 studies) was reported as the primary outcome measure Cramps were, among other secondary outcome measures, assessed in the so called Efficacy Evaluation (EE) population...using (Quote:) "the principle of last observation carried forward". The number of participants belonging to the EE at 12 months are not explicitly given. Neither are the actual number of assessments (i.e. minimally 1, maximally 4) or the date of the last examination before (i.e. at 3, 6, 9 or 12 months) termination (i.e. early versus regular termination) given, and a systematic difference in the 2 groups cannot be ruled out
Other bias	Low risk	Comment: no other bias was observed

Gil 1992.

Methods	Double‐blind, quasi‐randomised, placebo‐controlled cross‐over trial Assessment of cramps (patient's global impression of muscle cramp burden over the time between study visits as rated by VAS) at week 0, 1, 3, 5
Participants	20 participants (11 female, 9 male) with probable or definite ALS
Interventions	A: L‐threonine 2 g/day for 8 days B: L‐leucine 12 g/day + L‐isoleucine 8 g/day + L‐valine 6,4 g/day for 8 days C: placebo for 8 days Between phase A to B and B to C was a washout period of 8 days, respectively
Outcomes	Outcome measures (primary outcome measure not stated): manual muscle strength, a clinical severity score, a bulbar function score, and fatigue and cramps assessed on a VAS. Comment: cramp assessment by VAS was not further specified (i.e. not specified whether cramp intensity or number of cramp days were assessed) Quote: "Pour ce qui concerne les chelles d'auto‐evaluation, la fatigue, les fasciculations, le handicap ne sont pas modifies; toutefois, les crampes, stables sous acides amines branches et sous L‐threonine, s'aggravent sous placebo (P = 0,038)." Translation: "Concerning visual analogue scale of fatigue and fasciculation, the result remained unchanged. But cramps, stable under therapy with branched amino acids and L‐threonine, increased under placebo (P = 0.038)
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	High risk	Allocation generation to cross‐over sequence was not done by random but by sequential entry into the study: 1. participant to ABC, 2. to BCA, 3. to CAB, 4. again to ABC, etc. No comparison of baseline characteristics was given to document an even distribution among the groups
Allocation concealment (selection bias)	High risk	No information concerning allocation concealment is provided. Comment: probably not done
Blinding (performance bias and detection bias) All outcomes	Low risk	Quote: "Chaque traitement etait presente sous la meme forme galenique en suspension buvable de telle sorte que ni le medecin prescripteur, ni le malade ne puissent faire le difference entre les trois prescriptions..." Translation: "Each of the treatments consisted of an identically appearing soluble so that neither the prescribing physician, nor the patient could make out a difference between the three ..."
Incomplete outcome data (attrition bias) All outcomes	High risk	No information concerning incomplete data is provided
Selective reporting (reporting bias)	Unclear risk	Insufficient information to permit judgement
Other bias	Unclear risk	No formal stopping rule specified

Groeneveld 2003.

Methods	Double‐blind, randomised, placebo‐controlled parallel trial Assessment of cramps at week 0, 4, 8, 24, 40, 56
Participants	175 participants (57 female, 118 male) with probable or definite ALS
Interventions	Creatine 10 g/day Placebo
Outcomes	Primary outcome: death, tracheostomy, or persistent assisted ventilation after 16 months Secondary outcomes: rate of decline in muscle strength, rate of decline of lung VC, rate of decline of ALSFRS, and rate of decline of the physical and mental summary scores of the SF‐36 Cramps were assessed as adverse effects. Adverse effects were not significantly different between the groups
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Randomization was performed by an independent physician according to the minimization method of Pocock and Zelen."
Allocation concealment (selection bias)	Low risk	Quote: "After having allocated a trial patient to one of two treatment groups, Groups A or B, the independent physician, ignorant to whether A or B was creatine, would instruct the research pharmacist to prepare trial medication A or B. The research pharmacist was the only person who knew the trial code of A or B. Trial medication was packed in blank containers and handed out ..."
Blinding (performance bias and detection bias) All outcomes	Low risk	Quote: "... Polycose, an odourless glucose polymer resembling creatine monohydrate in colour and form." ... "the independent physician, ignorant to whether A or B was creatine, would instruct the research pharmacist to prepare trial medication A or B. The research pharmacist was the only person who knew the trial code of A or B. Trial medication was packed in blank containers..."
Incomplete outcome data (attrition bias) All outcomes	Low risk	In survival data, censoring is unlikely to be introducing bias
Selective reporting (reporting bias)	Low risk	The results of all outcome measures were reported
Other bias	Low risk	Comment: no other bias was observed

Lacomblez 1996.

Methods	Double‐blind, randomised, placebo‐controlled parallel trial Assessment of cramps (patient's global impression of muscle cramp burden over the time between study visits as rated by VAS) at week 0, 8, 16, 24, 32, 40, 48, 56, 64, 72, 80, 96, 104
Participants	959 participants (384 female, 575 male) with probable or definite ALS
Interventions	Riluzole 50 mg/day Riluzole 100 mg/day Riluzole 200 mg/day Placebo
Outcomes	Primary outcome: death or tracheostomy Secondary outcomes: rates of change in functional measures (muscle strength, functional status, respiratory function, and patient’s assessments of fasciculation, cramps, stiffness, and tiredness. Cramps expressed on 100 mm VAS Quote: "No other treatment effect was detectable with the other secondary variables (respiratory function test, visual analogue scales, or clinician general impression of severity)." No specific results concerning cramps were presented in the article
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "...Randomisation was stratified by centre..."
Allocation concealment (selection bias)	Low risk	Quote: "...Randomisation was stratified by centre..."
Blinding (performance bias and detection bias) All outcomes	Low risk	Quote: "...a double‐blind, placebo‐controlled, multicenter study...the four formulations were identical in appearance"
Incomplete outcome data (attrition bias) All outcomes	Low risk	Comment: incomplete data reported in detail
Selective reporting (reporting bias)	Low risk	Several secondary outcome measures were not reported but a statement that none of them differed statistically significant between the two groups was made
Other bias	Low risk	Comment: no other bias was observed

Lacomblez 1996a.

Methods	Double‐blind, randomised, placebo‐controlled parallel trial Assessment of cramps (patient's global impression of muscle cramp burden over the time between study visits as rated by VAS) at week 0, 8,16, 24, 32, 40, 48, 56, 64, 72 ,80, 96, 104 "... Rates of functional deterioration were secondary efficacy criteria. Disease progression was assessed with use of functional evaluations (muscle testing, modified Norris limb and bulbar scales) and symptom assessments for fasciculations, cramps, stiffness, and tiredness were based on the patients’ subjective evaluation using 100‐mm visual‐analog scales ..."
Participants	959 participants (384 female, 575 male) with probable or definite ALS
Interventions	Riluzole 50 mg/day Riluzole 100 mg/day Riluzole 200 mg/day Placebo
Outcomes	Primary outcome: death, tracheostomy, or mechanical ventilation after 18 months Secondary outcomes: muscle strength, modified Norris limb and bulbar scales, change of CGI, lung VC, and subjective symptom assessments for fasciculations, cramps, stiffness, and tiredness (using 100 mm VAS) Data concerning cramps were not given
Notes	Subgroup analysis of the study by Lacomblez 1996
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "... Randomisation was stratified by centre...".
Allocation concealment (selection bias)	Low risk	Quote: "... Randomisation was stratified by centre...".
Blinding (performance bias and detection bias) All outcomes	Low risk	Quote: "...identical tablets...".
Incomplete outcome data (attrition bias) All outcomes	Low risk	A detailed report is given in Lacomblez 1996
Selective reporting (reporting bias)	High risk	Incomplete reporting of secondary outcome measures. The results of some secondary outcome measures (fasciculations, cramps, stiffness, tiredness and CGI) were neither reported nor mentioned (e.g. being not statistically different)
Other bias	Low risk	Comment: no other bias was observed

Meininger 2004.

Methods	Double‐blind, randomised, placebo‐controlled parallel trial Assessment of cramps (patient's global impression of muscle cramp burden over the time between study visits as rated by VAS) at week 4, 8, 16, 32, 40, 48, 56, 64, 72 Quote: "The secondary efficacy outcome variables were VC, manual muscle testing, ALSFRS, Norris limb and bulbar scales, VAS (for fasciculations, cramps, stiffness, fatigability, and breathing),"... etc
Participants	867 participants (338 female, 529 male) with probable or definite ALS in the first, 1210 (448 female, 762 male) participants with probable or definite ALS in the second of the 2 studies reported in this article. "Patient characteristics at baseline...were similar between ... groups..."
Interventions	Study 1: xaliproden 1 mg/day xaliproden 2 mg/day placebo Identical‐appearing capsules once daily Study 2: xaliproden 1 mg/day + riluzole 100 mg/day xaliproden 2 mg/day + riluzole 100 mg/day placebo + riluzole 100 mg/day In addition to riluzole, participants were given identical‐appearing capsules once daily
Outcomes	Primary outcome: time to death, tracheostomy, or permanent assisted ventilation (DTP), and 2. Time to lung VC 50% or DTP Secondary outcomes: lung VC, muscle strength, ALSFRS, Norris limb and bulbar scales, VAS (using 100 mm VAS) for fasciculations, cramps, stiffness, fatigability, and breathing, spasticity scale, CGI (severity of illness, impression of change), and SIP. Results concerning cramps were not given
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "...A computer‐generated list was used to randomly assign patients to the three treatment arms..."
Allocation concealment (selection bias)	Low risk	Quote: "A double‐blind randomised parallel group design was used... At all sites consecutively enrolled individuals who satisfied all entry criteria received the next treatment number."
Blinding (performance bias and detection bias) All outcomes	Low risk	Quote: "...Patients were given identical‐appearing capsules..."
Incomplete outcome data (attrition bias) All outcomes	Low risk	Comment: discontinuations were reported in detail and were equally distributed among all groups
Selective reporting (reporting bias)	Low risk	The results of all outcome measures were reported
Other bias	Low risk	Comment: no other bias was observed

Miller 1996.

Methods	Double‐blind, randomised, placebo‐controlled parallel trial Assessment of cramps at week 0, 4, 8, 12, 16, 20, 24
Participants	149 participants (47 female, 102 male) with probable or definite ALS
Interventions	gabapentin 2400 mg/day placebo
Outcomes	Primary outcome: slope of arm strength megascore Secondary outcomes: rates of decline of lung functional VC and arm megascore slope for the completer population (those who had completed all 6 monthly visits) Cramps were assessed as adverse effects. Adverse effects were not significantly different between the groups
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "...patients were randomly assigned, ...". Comment: insufficient information to permit "Yes" or "No
Allocation concealment (selection bias)	Unclear risk	Comment: insufficient information to permit 'Yes' or 'No'
Blinding (performance bias and detection bias) All outcomes	High risk	Quote: "...patients were randomly assigned in a double‐blinded fashion...". Gabapentin at a dose of 2000 mg per day is expected and did result in statistically significant more fatigue. This carries a risk of unblinding
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Insufficient reporting of outcome data of participants who did not complete the study to permit judgement of ‘Yes’ or ‘No’
Selective reporting (reporting bias)	Low risk	The results of all outcome measures were reported
Other bias	Low risk	Comment: no other bias was observed

Miller 2001.

Methods	Double‐blind, randomised, placebo‐controlled parallel trial Assessment of cramps (patient's global impression of muscle cramp burden over the time between study visits as rated by VAS) at week 0, 4, 8, 12, 16, 20, 24, 28, 32, 36 Quote: "...as well as a symptom survey (cramps, fasciculations, stiffness, sleeping and emotionality, in which patients rated the severity of symptoms on an analogue scale of 0 to 10), were all measured every 4 weeks."
Participants	204 participants (79 female, 125 male) with probable or definite ALS Quote: "The baseline characteristics of the patients were...well matched for age, sex, height, weight, initial FVC, MVC (% predicted), and initial mean megascore. However, treated patients had a shorter duration of symptoms prior to study entry...compared with the placebo group suggesting a more rapid rate of progression in the treated group."
Interventions	Gabapentin 3600 mg/day Placebo Quote: "Eligible patients were randomly assigned in a double blinded fashion to receive either gabapentin 1,200 mg or placebo three times daily for 9 months."
Outcomes	Primary outcome: slope of arm strength megascore Secondary outcomes: lung VC, ALSFRS, timed walking, rapid foot taps, a health status survey, SF‐12 quality of life scale, as well as symptom surveys (cramps, fasciculations, stiffness, sleeping and emotionality, in which participants rated the severity of symptoms on an analogue scale of 0 to 10) Quote: "...there was no difference between the treatment and placebo groups with respect to...symptomatic benefit of...cramps..."
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "The randomisation was accomplished by the research pharmacist at the coordinating site and the allocation of patients was known only to her."
Allocation concealment (selection bias)	Low risk	Quote: "Randomization was accomplished in blocks of four patients, two placebo and two drug in each block, which equalized treatment assignment at each treatment centre."
Blinding (performance bias and detection bias) All outcomes	Low risk	Quote: "All capsules were identical in appearance."
Incomplete outcome data (attrition bias) All outcomes	Low risk	Comment: incomplete data reported
Selective reporting (reporting bias)	Low risk	Comment: although reported as assessed in the methods section, no results concerning cramps were presented in the article, but an analysis of secondary outcome measures revealed no difference between the groups Some results of the secondary outcome measures (e.g. symptom survey) were not reported, but it was stated that none of the secondary outcomes were statistically significantly different between the 2 groups
Other bias	Low risk	Comment: no other bias was observed

Norris 1979.

Methods	Double‐blind, randomised, placebo‐controlled parallel trial Assessment of cramps at week 0, 1, 2, 3, 4, 5, 6, 7
Participants	20 participants (gender not reported) with probable or definite ALS Participant characteristics were not reported.
Interventions	Baclofen 15 to 80 mg/day Placebo Quote: "23 consecutive patients with ALS ... who manifested major problems with spasticity were randomly assigned to treatment with either baclofen or placebo."
Outcomes	Outcome measures (primary outcome measure not stated): an ALS clinical score, subjective impression of spasticity and cramps Quote: "Several patients in the baclofen treated group noted ... diminution of painful cramps, but such benefit also occurred in the placebo‐treated patients."
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Insufficient information about the sequence generation process to permit judgement of ‘Yes’ or ‘No’
Allocation concealment (selection bias)	Unclear risk	Insufficient information about the sequence generation process to permit judgement of ‘Yes’ or ‘No’
Blinding (performance bias and detection bias) All outcomes	Unclear risk	Quote: "The present report concerns a short‐term, placebo‐controlled, double‐blind study..." No further information is given
Incomplete outcome data (attrition bias) All outcomes	High risk	No information concerning incomplete data is provided. Comment: probably not done
Selective reporting (reporting bias)	Unclear risk	Insufficient information to permit judgement
Other bias	Unclear risk	Insufficient information to permit judgement

Rosenfeld 2008.

Methods	Double‐blind, randomised, placebo‐controlled parallel trial Assessment of cramps at week 0, 1, 2, 3, 8, 12, 16, 20, 28, 36
Participants	107 participants (45 female, 62 male) with probable or definite ALS
Interventions	Creatine monohydrate 5 g/day Placebo
Outcomes	Primary outcome: MVIC Secondary outcomes: FVC, ALSFRS, SF‐12 quality of life scale and muscle fatigue Cramps were assessed as adverse effects. Adverse effects were not significantly different between the groups
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Patients were randomised in a 1:1 ratio..." and "Randomisation was organized in blocks and stratified by clinic to ensure treatment group balance at each site."
Allocation concealment (selection bias)	Low risk	Comment: done centrally
Blinding (performance bias and detection bias) All outcomes	Unclear risk	Insufficient information to permit 'Yes' or 'No'
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Insufficient reporting of outcome data of participants who did not complete the study to permit judgement of ‘Yes’ or ‘No’
Selective reporting (reporting bias)	Low risk	Study registered (NCT00069186) and primary and secondary outcome measures specified. Some results of the secondary outcome measures (e.g. symptom survey) were not reported, but it was stated that none of the secondary outcomes were statistically significantly different among the two groups
Other bias	Low risk	Comment: no other bias was observed

Scelsa 2005.

Methods	Double‐blind, randomised, placebo‐controlled parallel trial Assessment of cramps at week 0, 12, 24, 36
Participants	46 participants (13 female, 33 male) with probable or definite ALS
Interventions	Indinavir 800 mg/day Placebo
Outcomes	Primary outcome: slope of decline of the ALSFRS score Secondary outcomes: slope of decline of the Manual Muscle Testing Composite Scale score, lung VC, and the SF‐36 quality of life scale Cramps were assessed as adverse effects: the number of participants reporting leg muscle cramp as a side effect was (2/23, 8.7%) in the treatment group and (1/23, 4.4%) in the placebo group for the whole observation period. Adverse effects were not significantly different between the groups
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Patients were randomised 1:1 to placebo or indinavir treatment by the Beth Israel Pharmacy Department, using a random chart assignment."
Allocation concealment (selection bias)	Low risk	Quote: "Patients were randomised ... by the Beth Israel Pharmacy Department ..."
Blinding (performance bias and detection bias) All outcomes	Low risk	Quote: "All study personnel and patients were blinded to treatment. To maintain the blind, the neurologists assessing the outcome measures did not collect the adverse effect data."
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Insufficient reporting of outcome data of participants who did not complete the study to permit judgement of ‘Yes’ or ‘No’
Selective reporting (reporting bias)	Low risk	The results of all outcome measures were reported
Other bias	Low risk	Comment: no other bias was observed

Weber 2010.

Methods	Double‐blind, randomised, placebo‐controlled cross‐over trial Assessment of cramps at week 0, 4, 8 Quote: "The primary outcome measure was the average cramp intensity during the preceding 24 hours rated every morning on a VAS with a scale of 0 to 10 (zero to maximal burden, i.e. 0% to 100%).
Participants	22 participants (5 female, 17 male) with probable or definite ALS Due to the cross‐over study design, mean baseline participant characteristics were not compared between the placebo‐verum and the verum‐placebo group
Interventions	THC 10 mg/day for 2 weeks Placebo for 2 weeks Washout period of 2 weeks Quote: "The active study medication consisted of sesame oil containing D9‐THC (dronabinol) 2.5 mg. The placebo medication contained only sesame oil..."
Outcomes	Primary outcome: average cramp intensity during the preceding 24 hours rated every morning on a VAS Secondary outcomes: number of cramps during the preceding 24 hours, and severity of fasciculations on a VAS
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "A computer‐generated blockwise random sequence was provided by the study statistician."
Allocation concealment (selection bias)	Low risk	Quote: "Two copies of the complete randomisation list were prepared. One was used by the hospital pharmacy in conjunction with the patient’s trial number to dispense either THC and then placebo or vice versa. Another was stored at a confidential location by the statistician until the time of unblinding."
Blinding (performance bias and detection bias) All outcomes	Low risk	Quote: "All investigators and patients were blinded to treatment allocation for the duration of the study. ... The placebo medication contained only sesame oil and looked and tasted identical to the active medication."
Incomplete outcome data (attrition bias) All outcomes	Low risk	Comment: incomplete data adequately reported
Selective reporting (reporting bias)	Low risk	Study registered (NCT00812851) and primary outcome measure specified. The results of all outcome measures were reported
Other bias	Low risk	Comment: no other bias was observed

ALS/MND: amyotrophic lateral sclerosis/motor neuron disease

ALSFRS‐R: amyotrophic lateral sclerosis functional rating scale ‐ revised

CGI: clinical global impression

FVC%: forced vital capacity as a percentage of predicted

MRC: Medical Research Council

MVIC: maximum voluntary isometric contraction

SF‐12: Short Form‐12 Health Survey

SF‐36: Short Form‐36 Health Survey

THC: tetrahydrocannabinol

VAS: visual analogue scale

VC: vital capacity

Characteristics of excluded studies [ordered by study ID]

Study	Reason for exclusion
Aggarwal 2010	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Aisen 1995	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Aksu 2002	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Aksu 2002a	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
ALSCNTF 1996	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Apostolski 1998	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Appel 1988	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Aquilonius 1986	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Armon 1997	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Askmark 1993	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
BDNF 1999	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Beghi 1993	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Beghi 2000	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Bello‐Haas 2007	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Berto 2007	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Biletch 1989	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Blin 1991	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Blin 1996	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Borasio 1996	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Borasio 1998	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Bourke 2006	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Bradley 1984	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Brody 1974	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Brooke 1986	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Brooks 1985	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Brooks 1987	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Brooks 1995	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Brooks 2001	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Caroscio 1986	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Carter 2005	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Cedarbaum 1997	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Chiò 1998	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Civardi 1994	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Conrad 1985	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Cudkowicz 2003	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Cudkowicz 2006	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Cudkowicz 2008	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Desai 1998	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Di 2006	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Drachman 1994	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Drory 2001	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Drory 2002	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Eckland 1986	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Eisen 1993	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Ellis 1997	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Fareed 1971	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Farkkila 1990	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Farkkila 1996	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Finsterer 1999	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Gelinas 2001	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Goonetilleke 1995	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Gordon 2004	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Gordon 2006	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Gordon 2006a	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Gordon 2007	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Gordon 2008	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Graf 2005	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Gredal 1996	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Gredal 1997	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Groeneveld 2005	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Guiloff 1987	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Guiloff 1987a	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Hallett 1984	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Harrington 1984	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Hawley 1987	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Hesselmans 1993	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Hoagland 1997	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Hubbard 1992	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Imoto 1984	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Jackson 2001	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Janik 1996	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Jossan 1994	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Kaji 1998	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Kalra 2003	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Karageorgiou 2004	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Kaufmann 2009	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Kelly 2008	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Kodama 2000	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Kwiecinski 2001	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Lacomblez 1989	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Lacomblez 1989a	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Lacomblez 2002	Open label extension study (i.e. not randomized) of Bensimon 1994 and Lacomblez 1996 to assess long‐term safety of riluzole 100 mg/day.
Lacomblez 2004	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Lai 1997	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Lange 1996	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Lange 1998	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Lange 2006	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Lauria 2009	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Levin 2006	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Levy 2006	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Lipp 2003	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Liversedge 1956	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Lomen‐Hoerth 2007	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Louwerse 1995	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Markland 1997	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Mazzini 1994	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Mazzini 1998	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Meininger 1995	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Meininger 2006	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Meininger 2009	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Meyer 2008	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Miller 1996a	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Miller 1996b	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Miller 1996c	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Miller 1996d	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Miller 2007	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Mitchell 1995	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Mitsumoto 1986	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Munsat 1981	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Munsat 1987	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Munsat 1992	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Murphy 1995	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Nagano 2005	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Nefussy 2010	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Norris 1974	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Norris 1986	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Norris 1993	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Ochs 2000	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Oda 1996	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Olarte 1979	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Olarte 1985	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Olson 1978	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
On 2005	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Panitch 2006	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Pascuzzi 2010	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Percy 1971	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Piepers 2008	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Piepers 2009	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Pioro 2010	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Plaitakis 1988	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Pontieri 2005	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Poutiainen 1994	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Rabkin 2009	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
rHCNTF 1995	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
rHCNTF 1996	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Rivera 1979	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Rivera 1980	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Roufs 1991	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Ryberg 2003	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Sacca 2009	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Sato 2006	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Shefner 2004	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Smith 1986	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Smith 1993	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Sofuoglu 2008	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Sorenson 2008	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Steele 2007	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Strevic 1998	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Szczudlik 1998	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Tandan 1996	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Testa 1989	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Testa 1992	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Tyler 1978	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Tyler 1979	Neurotoxin was given intramuscularly
Yanagisawa 1997	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Zhang 2007	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Ziv 1994	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.
Zoccolella 2005	The study did not meet the selection criteria. "Cramp" or "cramps" was not mentioned in the full text paper.

Characteristics of ongoing studies [ordered by study ID]

Strong ongoing.

Trial name or title	Randomised crossover design trial of vitamin E vs placebo for treatment of cramps in amyotrophic lateral sclerosis
Methods	Double‐blind, placebo‐controlled, randomised, cross‐over trial
Participants	People with ALS/MND
Interventions	800 IE vitamin E twice daily vs placebo (cross‐over)
Outcomes	Primary outcome measure: reduction of cramp number in a 2‐week period (time frame: 4 weeks) Secondary outcome measure: reduction of cramp duration and severity in a 2‐week period (time frame: 4 weeks)
Starting date	December 2006
Contact information	Principal Investigator: Michael J Strong, MD, FRCPC. Sub‐Investigator: Christen L Shoesmith, MD, FRCPC. Contact: Ann Rowe, RN, 1‐519‐663‐3934 annm.rowe@lhsc.on.ca
Notes

ALS/MND: amyotrophic lateral sclerosis/motor neuron disease

Differences between protocol and review

1. The first search included the search terms "motor neuron disease", "cramp" and "clinical trial". After updating the first search a number of relevant studies which were retrieved during the first search were no longer identified. After omitting "cramp" as a search term, relevant studies from the first search were again identified but at the cost of expanding the search to all (randomised controlled) intervention trials (in ALS).

2. Primary outcome measure: we changed "absolute change in analogue rating scale of cramps one month after initiation of the intervention" to "reduction in the (patient's) global impression of muscle cramp burden over a period of time rated with a visual analogue scale (VAS)" since the vast majority of studies used this global measure and did not assess number, duration and intensity (or severity) of muscle cramps. Furthermore, no studies used a four‐week intervention period.

3. Secondary outcome measures: because the outcomes "duration of cramps" and "number of days/nights per week during which the participants had muscle cramps (cramp days)" were not used in any of the trials, we eliminated them. Since one study assessed the "cramp intensity in the last 24 hours" and "number of cramps in the last 24 hours", these outcome measures were included. Since quality of life and adverse effects are also important outcome measures likely to be assessed in studies primarily designed to treat cramps, we also included these.

4. After it became apparent that only few data could be retrieved from existing trials, we included studies using subcutaneous and intravenous medications (in addition to oral medication and physical therapy).

5. Change in authorship: Reto Baldinger and Hans Dieter Katzberg included; Daniel Feinberg withdrew.

Contributions of authors

MW drafted the protocol. RB performed data handling. All authors screened abstracts and articles meeting the inclusion criteria. RB drafted the final manuscript. All authors agreed on the risk of bias assessments for the included studies. MW and HK edited the final version and all authors agreed on the final version.

Sources of support

Internal sources

• Kantonsspital St. Gallen, Switzerland.

External sources

• Swiss ALS Foundation, Switzerland.

Declarations of interest

MW designed and conducted the study on THC for the treatment of cramps in ALS. He has not received any financial support or honoraria from the manufacturer. RB and HDK declare no known conflicts of interest.

New