Summary of findings
1 An isokinetic dynamometer was used in Aagaard 2005. A strain-gauge dynamometer was used in Gullestad 1992 and Poikolainen 2008.
2 All of the included trials demonstrated unclear and high risk of bias in at least one category.
3 Hand grip strength is an indirect measure of muscle weakness-related quality of life.
4 The total sample size is less than 400 (Cohen 1988) and the 95% confidence interval crosses the no-effect line.
Description of the condition
In the United States, alcohol dependence has an estimated lifetime and 12-month prevalence of 12.5% and 3.8% respectively (Hasin 2007). A 2004 survey of six European countries (Belgium, France, Germany, Italy, the Netherlands and Spain) estimated a lifetime and 12-month prevalence of 5.2% and 1.0% respectively (Alonso 2004). Moreover, 15% to 20% of primary care and hospitalised people have alcohol dependence and 8% have associated withdrawal symptoms (Dissanaike 2006; Foy 1995). The type and severity of symptoms of alcohol withdrawal syndrome (AWS) can vary between people and are positively correlated with the amount and duration of alcohol use. Initial minor withdrawal symptoms include insomnia, tremors, mild anxiety, gastrointestinal (GI) upset, headache, diaphoresis, palpitations, and anorexia, occurring within 6 to 12 hours after alcohol cessation (McKeon 2008). Approximately 7% of people with AWS can develop alcoholic hallucinations (visual, auditory, or tactile) 12 to 24 hours after the last alcohol consumption followed by tonic-clonic withdrawal seizures in 5% to 10% of them p after 24 to 48 hours. The most life-threatening complication of alcohol withdrawal is delirium tremens (DT), occurring in approximately 5% of people with AWS, with an associated mortality rate of 1% to 5%. Onset of DT is usually two to four days after withdrawal from alcohol but can also occur up to 14 days after. Symptoms during this time include hallucinations, disorientation, hypertension, tachycardia, low-grade fever, diaphoresis, increased respiratory rate, and agitation. People have an increased likelihood of developing DT if they have a pre-existing comorbidity, abnormal liver function, daily heavy alcohol use, older age, and previous history of DT or withdrawal seizures.
The Clinical Institute Withdrawal Assessment for Alcohol (CIWA) score is a validated scale that is the most commonly employed tool to measure withdrawal symptoms and to guide therapy (Sullivan 1989). The categories on this scale include sweating, anxiety, tremor, auditory or visual disturbances, agitation, nausea and vomiting, tactile disturbances, headache, and disorientation. Total symptom scores of more than 15 on this scale or a history of withdrawal seizures indicate that medications should be started at presentation. Unless delirium is present, medication is typically needed for no more than seven days after the last use of alcohol, although some people will report withdrawal symptoms, including sleep problems, for several more weeks. Protracted symptoms may precipitate relapse.
Description of the intervention
Both the standard and prophylactic treatments for people with AWS typically involve benzodiazepines, antipsychotics, folic acid, thiamine, and multivitamins (Mayo-Smith 1997; Mayo-Smith 2004; Vincent 2007). In a Cochrane overview (Amato 2011) of sedative benzodiazepines, anticonvulsants, baclofen, gammahydroxybutrate (GHB) and psychotropic analgesic nitrous oxide (PAN), only benzodiazepines performed better than placebo for people with AWS.
In some institutions magnesium sulphate is also given routinely or in response to hypomagnesaemia during the hospital stay where there is a risk of developing AWS or AWS is present (Beroz 1962; Shane 1991; Shulsinger 1977). A retrospective study of people with alcoholism in Seoul (Korea) Hospital showed that magnesium reduces the need for benzodiazepine therapy (Lee 2012). The study also showed that magnesium improves CIWA anxiety and sweating scores (Lee 2012). Nevertheless, current practice guidelines do not recommend routine administration of parenteral magnesium as existing controlled data do not demonstrate improvement in severity of alcohol withdrawal, delirium or seizures with its use (Mayo-Smith 2004). Different formulations, routes of administration, and doses have been reported in the literature as being used for alcohol withdrawal, from oral magnesium supplements for eight weeks to parenteral magnesium 8 to 16 mEq every four to six hours for 48 to 72 hours (Beroz 1962; Poikolainen 2008; Shane 1991; Shulsinger 1977; Wilson 1984).
How the intervention might work
Current literature suggests the following mechanisms of action for magnesium in people with AWS:
- Magnesium may have a moderating effect on elevated liver enzymes in alcoholics, and in theory may cause a decrease in the risk of death from alcoholic liver disease (Gullestad 1992; Poikolainen 2008). Gullestad et al suggest that magnesium is "essential in the maintenance of membrane integrity, which may be of importance in the protection from liver cell damage."
- Hyperfunctioning of glutamatergic pathways is posited as an explanation for AWS (Prior 2011). Hyperfunctioning, mainly through N-methyl-D-aspartate (NMDA) receptors, causes an excitotoxic influx of calcium and an increase in oxygen free radicals (Prior 2011). The resulting neural damage manifests as AWS. Magnesium cations may mitigate neural damage by competing with glumate's NMDA receptor binding site (Prior 2011).
- Since several studies have correlated serum magnesium levels with severity of depression (see Murck 2002 for review), magnesium supplementation may regulate anxiety and depression during alcohol withdrawal. The antidepressant and anxiolytic effects of magnesium are in line with its NMDA antagonistic property; that is, NMDA antagonism at the level of the hypothalamus decreases hypothalamic-pituitary-adrenal (HPA) activity (Murck 2002), a known marker for affective disorders (Holsboer 2000).
The relation between magnesium level and alcohol ingestion was first demonstrated in the 1950s (Flink 1954; Flink 1956). In a series of experiments in the 1960s, it was found that in people with alcohol dependence the severity of delirium tremens (DT) symptoms was correlated with the degree of hypomagnesaemia measured (Embry 1987; Suter 1955). This relation was also found when magnesium levels were measured from cerebrospinal fluid (Glickman 1962; Mendelson 1969). The mechanism for this phenomenon was subsequently studied. In some studies, it was demonstrated that alcohol administration led to an acute increase in magnesium excretion in the range of 167% to 260% greater than for control subjects. Furthermore, decreased oral intake secondary to chronic alcoholism would also contribute to decreased magnesium levels (Jermain 1992). The authors also found a correlation between chronic alcoholism and low muscle magnesium levels. An increase in long chain free fatty acids has been described in people experiencing DT (Mays 1970). It is thought that these acids bind magnesium and thus lower the amount of free circulating magnesium in the blood. A correlation has also been found during alcohol withdrawal between hypomagnesaemia and sinus tachycardia (Shane 1991).
While hypomagnesaemia is a common finding in people undergoing AWS, it is unclear whether they are directly related or are two concurrent conditions occurring independently of each other. This distinction is further complicated by the similarity in signs and symptoms of the two conditions. For example, people with magnesium deficiency tetany but without AWS can present with spasms of facial muscles and extremities, convulsions, and laryngeal stridor (Jermain 1992). Other research disputing the correlation between hypomagnesaemia and AWS includes findings where the serum magnesium level returns to normal spontaneously before DT develops (Mendelson 1959; Victor 1973). In Martin 1959, it was found that there was no correlation between serum magnesium concentrations and hallucinations and severe tremors in people with AWS. Some authors (Jermain 1992) have concluded that there is no causal relationship between hypomagnesium and AWS, and that "routine administration of parenteral magnesium sulfate in patients with DT is not recommended."
Why it is important to do this review
Despite the controversial theories behind the correlation between hypomagnesaemia and AWS, magnesium is being used empirically at many institutions for people with AWS. Some institutions include magnesium as part of their alcohol withdrawal protocol, while others do not. Some authors have justified the use of magnesium in all patients as “magnesium is relatively safe”. On the other hand, it is unknown if magnesium treatment leads to harm, which may include serious adverse effects of magnesium such as central nervous system (CNS) depression, arrhythmias, heart block, hypotension, respiratory tract paralysis, coagulopathies, and hyporeflexia.
To assess the effects of magnesium treatment/prophylaxis on the severity, duration, and progression of symptoms of alcohol withdrawal syndrome (AWS) in people hospitalised with AWS or those who are at risk of developing AWS.
Criteria for considering studies for this review
Types of studies
Randomised controlled trials (RCTs). If full reports of trials were unavailable, we contacted the authors to obtain the information.
Types of participants
Hospitalised adults with a current history of alcohol dependence, at risk for or already in acute withdrawal.
Types of interventions
Any formulation, route of administration, or dose of magnesium in addition to standard of usual care. The comparator was placebo (usual standard of care).
Types of outcome measures
- Number of participants with at least one seizure;
- Number of participants who developed a first episode of delirium tremens (DT) (resolution and prevention of occurrences);
- Number of participants who achieved a Clinical Institute Withdrawal Assessment for Alcohol (CIWA) score of 10 points or less.
- Serious adverse events;
- Organ dysfunction (cardiac, renal, respiratory depression);
- CIWA score components: nausea/vomiting, hallucinations, disorientation, hypertension, tachycardia, low-grade fever, diaphoresis, increased respiratory rate, and agitation;
- AWS severity;
- Muscle weakness;
- Total adverse events;
- Use of sedatives/psychotropics/phenytoin;
- Length of hospital stay;
Search methods for identification of studies
The searches incorporated a number of methods to identify completed or ongoing studies.
We searched the following electronic databases:
- The Cochrane Drugs and Alcohol Group Specialised Register (August 2012);
- The Cochrane Central Register of Controlled Trials (CENTRAL; The Cochrane Library 2012, issue 8);
- PubMed (from 1966 to August 2012);
- EMBASE (from 1988 to August 2012);
- CINAHL (from 1982 to March 2010);
- Web of Science (1965 to August 2012).
We searched the databases using a strategy developed incorporating the filter for the identification of RCTs (Cochrane Handbook) combined with selected MeSH terms and free-text terms relating to alcohol withdrawal syndrome. The PubMed search strategy was modified for the other databases using the appropriate controlled vocabulary.
We searched for ongoing clinical trials and unpublished studies with Internet searches on the following sites:
- ClinicalTrials.gov (www.clinicaltrials.gov);
- WHO International Clinical Trials Registry Platform (ICTRP) (http://apps.who.int/trialsearch/);
- Current Controlled Trials (http://www.controlled-trials.com/);
- CenterWatch Clinical Trials Listing Service (http://centrewatch.com).
Searching other resources
We also searched:
- References of the articles obtained by any means;
- Conference proceedings likely to contain trials relevant to the review;
- Contacting investigators and relevant trial authors seeking information about unpublished or incomplete trials.
All searches included non-English language literature, and non-English studies with English abstracts were assessed for inclusion. We translated studies considered likely to meet the inclusion criteria.
Data collection and analysis
Selection of studies
We assessed reports identified by the electronic searches for relevance based on a screening of titles and abstracts. Two review authors (AC and IK) independently inspected all study citations identified by the initial electronic searches, and obtained full reports of the studies of agreed relevance. Where there was disagreement, we acquired the full reports for more detailed scrutiny and consulted a third author to resolve disputes (AT). The review authors (AC and IK) then independently inspected all full study reports. We contacted the correspondence investigator if the necessary information was not available in the reports. An updated search was conducted in August 2012. All citations identified in the updated search were screened by one author (MS). Two authors (MS and AT) then screened full text articles identified studies that needed further review priot to inclusion.
Data extraction and management
Once all studies had been identified, the two review authors who had performed the original screening examined in detail those which fulfilled the inclusion criteria,using a standardised data extraction form.
Assessment of risk of bias in included studies
The 'risk of bias' assessment for RCTs and controlled clinical trials (CCTs) in this review was performed using the criteria recommended by the Cochrane Handbook for Systematic Reviews of Interventions (Cochrane Handbook). The recommended approach for assessing risk of bias in studies included in Cochrane reviews is a two-part tool, addressing seven specific domains, namely sequence generation and allocation concealment (selection bias), blinding of participants and providers (performance bias), blinding of outcome assessor (detection bias), incomplete outcome data (attrition bias), selective outcome reporting (reporting bias), and other possible sources of bias. The first step is to describe what was reported to have happened in the study, and the second is to assign a judgement about the risk of bias for that domain as being at low, high or unclear risk. To make these judgements we used the criteria set out in the Cochrane Handbook but adapted to the addiction field. See Table 1 for details.
We addressed the domains of sequence generation and allocation concealment (avoidance of selection bias) by a single entry for each study.
Incomplete outcome data (avoidance of attrition bias) were assessed separately for results at the end of the study period and for results at follow-up.
Measures of treatment effect
We analysed dichotomous outcomes by calculating the risk ratio (RR) for each trial, with the uncertainty in each result expressed with a 95% confidence interval (CI). Continuous outcomes were to be analysed by calculating the standardised mean difference (SMD) with a 95% CI. For outcomes assessed by scales we compared and pooled the mean score differences from the end of treatment to baseline (post minus pre) in the experimental and control groups.
Unit of analysis issues
Data from all patients individually randomised to each intervention were used in the analyses. We took care to identify situations where data were censored or excluded, and to distinguish between the total number of events and the total number of patients with a first event.
Dealing with missing data
In general if there were missing data, we contacted the authors of the study for clarification.
Assessment of heterogeneity
We conducted assessments for heterogeneity across the studies using the I² statistic (taking a threshold of 30% to 60% as indicating important heterogeneity) and the Chi² statistic (with statistical significance set at P < 0.10) (Cochrane Handbook; Higgins 2003). We explored clinical and methodological possible sources of heterogeneity, considering various study characteristics, including baseline risk factors for the outcomes of interest, duration of studies, age, type of magnesium, and gender distribution of participants across the studies.
Assessment of reporting biases
We planned sensitivity analyses to explore the implications of assuming that missing data were associated with a poor outcome or were imputed. The potential impact of missing data is addressed in the Discussion section.
We used Cochrane Review Manager 5.1 software for all data analyses, basing quantitative analyses of outcomes on intention-to-treat results (i.e. including all participants randomised to their original groups). We used risk ratios (RRs) and the random-effects model to combine outcomes across trials. For all dichotomous outcomes we calculated absolute risk reduction (ARR = risk difference x 100), and numbers needed to treat for benefit (NNTB = 1/risk difference).
Subgroup analysis and investigation of heterogeneity
We had planned to perform the following subgroup analyses:
- Participants with low serum magnesium levels versus those with normal/elevated serum magnesium levels.
- Previous co-morbidities, specifically cardiovascular disease and renal dysfunction.
- Studies that enrolled participants experiencing AWS versus studies that enrolled those at risk of AWS.
- Participants with severe comorbid diseases versus mild to moderate comorbid diseases, as measured with appropriate validated scales.
We had planned sensitivity analysis to test for the robustness of the results, including the following analyses:
1. Trials with acceptable randomisation or concealment of allocation compared to those without.
2. Trials preformed with intention-to-treat analysis compared to those without.
3. Unblinded versus blinded trials.
4. Different doses of magnesium.
5. Different routes of administration.
6. Number of doses of magnesium.
Our meta-analysis was not amenable to the planned subgroup and sensitivity analyses, as we had too few included studies to explore these variations.
Description of studies
Results of the search
Of the 278 unique records retrieved by the search, we excluded 217 on the basis of title and abstract and a further 57 records on the basis of a full-text reading. We included the remaining four records for a qualitative analysis.
Four studies, with a total of 317 participants, were included in our review (see Figure 1). Seventy-two per cent of the participants were men,and mean ages across the studies ranged from 41 to 57.
|Figure 1. Study flow diagram.|
Three trials (Aagaard 2005; Gullestad 1992; Poikolainen 2008) studied oral magnesium, with doses ranging from 12.5 mmol mg/day to 20 mmol mg/day. One trial (Wilson 1984) studied parenteral magnesium (16.24 mEq Mg sulphate IM q6h for 24 hours).
Two trials (Aagaard 2005; Poikolainen 2008) recruited participants from a hospital setting, one (Wilson 1984) from an outpatient clinic, while the fourth (Gullestad 1992) recruited from both a hospital and an outpatient clinic.
Countries of Origin
See Characteristics of included studies table for further details.
Of the 61 studies that we considered for a full-text review, 57 were excluded for the following reasons:
- Many (32) were not performed in people with alcohol dependence.
- Many (20) did not trial magnesium.
- In three studies, magnesium was not the only intervention.
- A few were not randomised controlled trials.
- Gisselman 1982 was not for acute withdrawal; all participants had been abstinent for at least three months.
See Characteristics of excluded studies table for reasons for exclusion.
Risk of bias in included studies
|Figure 2. Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.|
|Figure 3. Risk of bias summary: review authors' judgements about each risk of bias item for each included study.|
Random sequence generation
Two studies were assessed as having unclear risk of bias, as it was stated that participants were randomised but without describing the methods (Aagaard 2005; Gullestad 1992). The other two trials were assessed as being at low risk of bias, as the randomisation sequence was acceptable and described in sufficient detail (Poikolainen 2008; Wilson 1984)
Three included studies were assessed as being at unclear risk of bias, as only Aagaard 2005 reported concealment procedures in sufficient detail.
Three studies were deemed to have an unclear risk of bias, as they either reported a double-blind protocol but without describing the method (Gullestad 1992; Poikolainen 2008), or they provided no information about blinding (Aagaard 2005). Only one trial described blinding in sufficient detail to be assessed as being at low risk of bias for this domain (Wilson 1984).
Incomplete outcome data
Three trials (Gullestad 1992, Poikolainen 2008, Wilson 1984) were determined to be at high risk of bias for incomplete reporting of outcome data, as participants were lost to follow-up without explanation. The trial authors did not respond to our requests for the missing data.
Effects of interventions
Most of our outcomes of interest were not covered by the included studies. Among the secondary outcomes, only muscle strength was reported by three trials and was amenable to meta-analysis (see Appendix 7).
The primary outcomes studied were muscle mass (no significant difference between groups) and muscle strength.
Muscle mass, measured by a formula that uses 24-hour urinary creatinine, increased by 11% in both groups (14.7+/-0.9 kg baseline to 16.3+/-0.8 kg; P = 0.05) (no statistical comparison between groups).
Muscle strength, measured by an isokinetic dynamometer, increased by 14% in both groups (106+/-6 Nm baseline to 121+/-6 Nm; P < 0.001) (no statistical comparison between groups).
Additionally, the study did not find statistically significant differences for the following secondary outcomes: serum bilirubin, serum albumin, and plasma alkaline phosphate.
The study reported prothrombin times but did not report on bleeding rates.
Statistically significant differences between the magnesium group and the placebo group were found at the end of the study for the following outcomes:
- Participants in the magnesium group had higher levels of sodium, potassium, and magnesium.
- Liver Enzymes
- Participants in the magnesium group had lower levels of both aspartate aminotransferase and alanine aminotransferase.
Additionally, in the magnesium group, maximal handgrip strength, measured by a strain-gauge dynamometer, increased significantly from baseline ((54+/-29 bar to 62+/-33 bar; P < 0.05) and (52+/-31 bar to 57+/-32 bar; P < 0.01) for right and left hand, respectively) while in the placebo group maximal handgrip strength remained unchanged.
The study reported on blood pressure changes, but not on participants experiencing hypotensive episodes.
An intention-to-treat analysis found no difference between groups in any outcomes measured. An analysis of study completers (27 of 64 allocated to magnesium and 31 of 54 allocated to placebo) found significant differences between groups for the following outcomes:
- After controlling for baseline serum magnesium levels, coffee consumption and non-compliance, participants in the treatment group were found to have higher levels of serum magnesium.
- Liver Enzymes
- After controlling for age, body weight, baseline alcohol intake, subsequent change in alcohol intake and baseline serum aspartate aminotransferase (S-AST), participants in the treatment groups were found to have lower levels of S-AST.
They measured handgrip strength with a strain-gauge dynamometer, but found no differences between intervention and placebo groups for either right or left hand comparisons (P = 0.445 and 0.436 for right and left hand respectively). It should be noted that this analysis was based on fewer than half the randomised population (i.e. people that completed the study).
People in the treatment group had higher levels of serum magnesium. This significant difference was transient, however, with no difference between groups 48 hours after intramuscular administration of magnesium. As participants were discharged, they were excluded from analysis of serum magnesium. Sufficient participants were available for analysis up to 72 hours post-dose, but more than 20% were lost by 96 hours post-dose.
Three of 50 participants in each group developed delirium tremens. Two of 50 participants in the magnesium group developed grand mal seizures, compared with three of 50 in the placebo group. No statistically significant differences were found, but this trial may have been underpowered for these outcomes.
The investigators reported no difference in alcohol withdrawal symptoms between groups (no statistical analysis provided) based on an investigator-developed withdrawal rating scale that included several variables (diaphoresis, tremor, vomiting, hallucinations, withdrawal severity, grand mal seizures, delirium tremens) in common with the CIWA rating scale.
The investigators reported no difference in the amounts of first-24 hour (P > 0.10), post-24 hour (P > 0.10) and total (P > 0.10) chlordiazepoxide required to control AWS. Again, the trial may have been underpowered for these outcomes.
Three studies (Aagaard 2005; Gullestad 1992; Poikolainen 2008) measured differences in muscle strength between participants who received magnesium or placebo. The meta-analysis detected no statistical heterogeneity or statistically significant difference in muscle strength (as measured by isokinetic and strain-guage dynamometer) between the magnesium and placebo groups (standardised mean difference (SMD) 0.04; 95% confidence interval (CI) -0.22 to 0.30, Analysis 1.1; Figure 4).
|Figure 4. Forest plot of comparison: 1 Magnesium versus placebo, outcome: 1.1 Muscle strength.|
Magnesium is being used in practice in the prevention and treatment of alcohol withdrawal. The degree of use is varied, with some clinicians routinely treating all people admitted with alcohol withdrawal, some using it only in people with low serum magnesium levels, and some not at all. It is hypothesised that the decrease in magnesium causes symptoms of alcohol withdrawal and possibly death. Possible mechanisms include: decreased magnesium intake, increased magnesium excretion, increased concentration of magnesium-binding fatty acids, and modification of liver enzyme elevation. However, there are also conflicts within the literature about the role of magnesium and its utility for alcohol withdrawal.
Summary of main results
Only one included study (Wilson 1984) measured at least one of the primary outcomes specified in our protocol. Of the secondary outcomes identified, only muscle weakness (strength) was measured in three of the four included trials that allowed for meta-analysis. However, the effect did not show a statistically significant difference in muscle strength between magnesium supplementation and placebo.
The included trials did not provide sufficient harms data for meta-analysis; the risk of serious adverse events for magnesium (such as central nervous system (CNS) depression, arrhythmias, heart block, hypotension, respiratory tract paralysis, coagulopathies, and hyporeflexia) remains uncertain.
Overall completeness and applicability of evidence
Only Wilson 1984 measured clinical symptoms of seizure, delirium tremens or components of the Clinical Institute Withdrawal Assessment for Alcohol (CIWA) score. However, it suffers from many limitations and describes participant populations and practices more than 20 years ago, some of which may not be applicable to present management of alcohol withdrawal. The one secondary outcome, reported in three trials, that could be meta-analysed was muscle strength. However, this result should be interpreted with caution, as it is a surrogate marker for alcohol withdrawal complications, and confounding factors in measuring this outcome were not addressed or accounted for in any of the trials.
Quality of the evidence
The overall quality of the evidence is poor. All four included trials demonstrated unclear or high risks of bias in at least one domain. There was significant clinical heterogeneity in the studies pooled for meta-analysis for participant population; diagnosis of alcohol dependence; inclusion criteria; type, dose and duration of magnesium treatment; and type of treatment facility. While the degree of clinical and methodological variation between the studies is high, the I² value (0%) of our meta-analysis seems to indicate low statistical heterogeneity (Cochrane Handbook). However, given that the meta-analysis included few studies of small size, our I² value is not a reliable indicator of heterogeneity.
Potential biases in the review process
We could not obtain additional information from authors of trials where risk of bias was unclear. We were unable to evaluate a trial published in Russian (Enmin 1969), as no translation was possible.
Although we specified subgroups and proposed sensitivity analyses a priori, the paucity of retrieved studies and the heterogeneity of outcomes measured meant we could not perform meaningful subgroup or sensitivity meta-analysis.
Agreements and disagreements with other studies or reviews
Clinical practice guidelines published in 2004 do not recommend treatment of alcohol withdrawal delirium with magnesium, but they do report a suggestion of decreased neuromuscular activity with magnesium administration (Mayo-Smith 2004). The guideline recommendation to correct electrolyte abnormalities, including magnesium deficiency, stems from expert opinion and biological rationale.
Implications for practice
There is currently insufficient evidence to support the routine use magnesium for prophylaxis or treatment in people experiencing or at risk of alcohol withdrawal. There is also insufficient evidence for magnesium treatment or prophylaxis in people with low serum magnesium experiencing or at risk of alcohol withdrawal .
Nevertheless, current practice guidelines recommend "that fluid status and electrolyte levels be monitored carefully and any abnormalities be corrected" (Mayo-Smith 2004).
Implications for research
Further research is needed to determine the role of magnesium in the prevention and treatment of alcohol withdrawal syndrome (AWS). A major limitation of this review was the paucity and heterogeneity of the studies' reported outcomes. The optimal trial would be randomised and placebo-controlled, with adequate power to detect a statistically significant difference in the important complications of AWS (i.e. death, seizures and delirium tremens). Since the symptomatology of AWS is varied, it would be best captured by validated symptom scales such as the CIWA score. Total adverse events and serious adverse events are probably the appropriate outcomes for safety data.
Stephen Adams for assistance in retrieving articles.
Data and analyses
- Top of page
- Summary of findings [Explanations]
- Authors' conclusions
- Data and analyses
- Contributions of authors
- Declarations of interest
- Sources of support
- Differences between protocol and review
- Index terms
Appendix 1. CDAG Specialized Register search strategy
Alcohol* AND (magnesium OR MgSO4)
Appendix 2. CENTRAL search strategy
- MeSH descriptor Alcohol-Related Disorders explode all trees
- MeSH descriptor Substance Withdrawal Syndrome explode all trees
- (#1 OR #2 OR #3)
- MeSH descriptor Magnesium Sulfate explode all trees
- MeSH descriptor Magnesium explode all trees
- (( #5 AND or#6 ) OR #7 OR #8)
- (#4 AND #9)
Appendix 3. PubMed search strategy
- Alcohol-related disorders[MeSH]
- Alcohol-Induced Disorders, Nervous System [MeSH]
- ((alcohol*[tiab] ) AND (disorder*[tiab] OR withdr*[tiab] OR abstinen*[tiab] OR abstain*[tiab] OR detox*[tiab] OR neuropathy[tiab] ))
- #1 OR #2 OR #3
- Magnesium Sulfate[MeSH]
- Magnesium [tiab]
- #5 OR #6 OR #7 OR #8
- randomized controlled trial [pt]
- controlled clinical trial [pt]
- randomized [tiab]
- placebo [tiab]
- drug therapy [sh]
- randomly [tiab]
- trial [tiab]
- groups [tiab]
- #10 OR #11 OR #12 OR #13 OR #14 OR #15 OR #16 OR #17
- animals [mh] NOT humans [mh]
- #18 NOT #19
- #4 AND #9 AND #20
Appendix 4. EMBASE search strategy
- (alcohol*:ab,ti AND (disorder*:ab,ti OR withdr*:ab,ti OR abstinen*:ab,ti OR abstain*:ab,ti OR detox*:ab,ti OR neuropathy:ab,ti))
- #1 OR #2
- 'magnesium sulfate'/exp
- magnesium:ab,ti OR mgso4:ab,ti
- #4 or #5 or #6
- 'crossover procedure'/exp
- double blind procedure'/exp
- 'single blind procedure'/exp
- 'controlled clinical trial'/exp
- 'clinical trial'/exp OR
- placebo:ab,ti OR 'double blind':ab,ti OR 'single blind':ab,ti OR assign*:ab,ti OR allocat*:ab,ti OR volunteer*:ab,ti
- random*:ab,ti OR factorial*:ab,ti OR crossover:ab,ti OR (cross:ab,ti AND over:ab,ti)
- 'randomized controlled trial'/exp
- #8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14 OR #15
- #3 AND #7 AND #16 AND [humans]/lim AND [embase]/lim
Appendix 5. CINAHL search strategy
- MH Alcohol-related disorders
- AB ((alcohol) and (disorder* or withdr* or abstinen* or abstain* or detox* or neuropathy))
- TI ((alcohol) and (disorder* or withdr* or abstinen* or abstain* or detox* or neuropathy))
- S1 OR S2 OR S3
- MH 'Dietary Supplements'
- MH Magnesium Sulfate
- TX Magnesium
- TX MgSO*
- S5 or S6 or S7 or S
- MH 'Animals' not (MH 'Animals' and MH 'Humans')
- S4 and S9
- S11 not S10
Appendix 6. ISI Web of Science search strategy
- Topic=((disorder* OR withdr* OR abstinen* OR abstain* OR detox* OR neuropathy))
- Topic=((magnesium OR MgSO4))
- #1 AND #2 AND #3
Timespan=All Years. Databases=SCI-EXPANDED, SSCI, A&HCI.
Appendix 7. Effects of interventions
Contributions of authors
I Fan Kuo: protocol development, search screening, study selection, interpretation of the data.
Juliana Li: protocol development, search screening, study selection, interpretation of the data.
Alice Chan: protocol development, search screening, study selection, interpretation of the data, writing/revising final review.
Michael Sarai: Search screening, study selection, interpretation of the data, writing/revising final review.
Aaron M Tejani: protocol development, search screening, study selection, interpretation of the data, writing/revising final review.
Declarations of interest
None to declare.
Sources of support
- Office support provided by the Therapeutics Initiative at the University of British Columbia, Canada.
- No sources of support supplied
Differences between protocol and review
Minor changes in Objectives section to reflect recommended format.
Medical Subject Headings (MeSH)
Administration, Oral; Alcohol Withdrawal Delirium [drug therapy]; Alcohol Withdrawal Seizures [drug therapy]; Alcoholic Beverages [*adverse effects]; Central Nervous System Depressants [adverse effects]; Ethanol [adverse effects]; Hand Strength; Hospitalization; Magnesium [*administration & dosage; blood]; Magnesium Sulfate [administration & dosage]; Randomized Controlled Trials as Topic; Substance Withdrawal Syndrome [blood; *drug therapy; prevention & control]
MeSH check words
Adult; Female; Humans; Male; Middle Aged