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Magnesium for alcohol withdrawal

  1. Michael Sarai1,
  2. Aaron M Tejani2,*,
  3. Alice Hill Wah Chan3,
  4. I Fan Kuo4,
  5. Juliana Li5

Editorial Group: Cochrane Drugs and Alcohol Group

Published Online: 5 JUN 2013

Assessed as up-to-date: 13 JUL 2012

DOI: 10.1002/14651858.CD008358.pub2


How to Cite

Sarai M, Tejani AM, Chan AHW, Kuo IF, Li J. Magnesium for alcohol withdrawal. Cochrane Database of Systematic Reviews 2013, Issue 6. Art. No.: CD008358. DOI: 10.1002/14651858.CD008358.pub2.

Author Information

  1. 1

    University of British Columbia, Department of Pharmaceutical Sciences, Vancouver, BC, Canada

  2. 2

    University of British Columbia, Therapeutics Initiative, Vancouver, BC, Canada

  3. 3

    Alberta Health Services, Edmonton, AB, Canada

  4. 4

    UBC, Vancouver, BC, Canada

  5. 5

    Fraser Health Authority, Clinical Research and Drug Information, Burnaby, Canada

*Aaron M Tejani, Therapeutics Initiative, University of British Columbia, 2176 Health Sciences Mall, Vancouver, BC, V6T 1Z3, Canada. Aaron.Tejani@fraserhealth.ca.

Publication History

  1. Publication Status: New
  2. Published Online: 5 JUN 2013

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Characteristics of included studies [ordered by study ID]
Aagaard 2005

MethodsRandomisation: placebo-controlled, parallel-group

Drop-outs in placebo group: 10/34

Drop-outs in treatment group: 7/25


ParticipantsN = 59 randomised (49 men); mean age = 49 (range:34 - 61)

Recruitment Setting: hospital department of hepatology and gastroenterology in Denmark

(1) Diagnosed with alcoholic liver disease (diagnosis based on liver biopsy or clinical, biochemical and ultrasonographic criteria)

(2) Mean alcohol consumption of 187g/day (range: 60 - 480 g/day); all participants had mean daily alcohol consumption of at least 60 g/day for minimum of 5 years

(3) Median time of abstinence was 1 week; 30 participants had been abstinent for less than 3 weeks before baseline examinations; 15 were consuming alcohol during the study, but had reduced their daily alcohol consumption (from 140 g/day to 20 g/day)

(4) 41% of the Mg-treated participants had taken spironolactone for two weeks or more prior to study entry; 22% of the placebo-treated had done so.


InterventionsTreatment: 2 X 8-hr infusion of Mg (30 mmol MgSO4 dispensed in 11 of glucose solution 55 g/L) and six weeks of Mg (6.25 mmol Mg BID) supplementation

Control: 2 X 8-hr infusion of glucose solution and six weeks of twice-daily placebo tablet.


OutcomesSkeletal muscle content of Mg

Maximum isokinetic muscle strength

Skeletal muscle mass

Skeletal muscle content of Na/K pumps

Serum bilirubin

Plasma alkaline phosphatase

Prothrombin index

Serum albumin.


NotesExclusion criteria: Non-alcoholic liver disease, encephalopathy, neurological, psychiatric or severe cardiopulmonary disturbances, malignancies, insulin-dependent diabetes mellitus, chronic diarrhoea, renal failure, thyroid disease, skeletal muscle disease

Muscle strength data: used muscle strength data for non-dominant knee which was measured using an isokinetic dynamometer.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuotes: "patients were randomised to receive Mg or placebo treatment"; "The randomisation code was unknown to the investigators until the end of the data analysis"; "41 % of the Mg-treated patients had taken spironolactone for 2 weeks or more prior to study entry, whereas only 22% of the placebo-treated patients had done so"

Comment: Although the study mentions a randomisation "code," the study fails to describe the process of randomisation adequately.

Allocation concealment (selection bias)Low riskQuote: "The randomisation code was unknown to the investigators until the end of the data analysis"

Blinding (performance bias and detection bias)
All outcomes
Unclear riskComment: While the randomisation code was concealed, information about blinding is not reported. Blinding was probably not done

Incomplete outcome data (attrition bias)
All outcomes
Low riskQuotes: "One randomised, placebo-treated patient was withdrawn from the study because of cancer, leaving only 33 patients in the placebo-treated group. Sixteen patients {7/25 Mg group+9/34 placebo group dropouts) were not examined at the end of the trial, which in 15 patients was due to lack of compliance. In one patient the biopsy material was unusable for technical reasons. Forty-two patients (18 Mg group+24 placebo group) completed the study"; "Two of the Mg-treated patients received the drug for only 5/6 weeks. One patient was readmitted to the hospital after 5 weeks without the study medicine, and we chose to do the
examinations at that point. The other patient wanted to abandon the medication but agreed to have the study exit examinations done"

Comment: Number of drop-outs is comparable across groups; reasons for drop-outs are also comparable (i.e. non-compliance); analysis was done on participants who failed to complete the entire trial but it is not clear if the outcomes of the 16 patients who were not examined were accounted for. The author did not respond to our request for drop-outs' missing data.

Gullestad 1992

MethodsRandomisation: placebo-controlled, double-blinded, block of 8

Drop-outs in placebo group: 3/25

Drop-outs in treatment group: 0/27


ParticipantsN = 52 randomised; mean age = 57 (range: 28 - 84)

Recruitment Setting: outpatient clinics and hospital in Norway

(1) participants had history of continuous or periodic heavy alcohol abuse for at least 10 years

(2) recruits from hospital were admitted for alcohol withdrawal syndrome, pancreatitis or alcohol intoxication.


InterventionsTreatment: six weeks of 5 mmol Mg-citrate-lactate tablets TID

Control: matching placebo


OutcomesLiver function tests (GGT, ASAT, ALAT, bilirubin, ALP)

Haematological parameters (Hgb, white blood cells, MCV, platelets)

Electrolytes (Na, K, Cl, Ca)

Muscle strength (handgrip strength, as measured by a strain-grip dynamometer)

Blood pressure and heart rate

Side effects (general wellbeing, fatigue)


NotesExclusion criteria: serum creatinine > 150 pmol/litre, cardiac AV conduction disturbances, and prior magnesium supplementation

Muscle strength data: used data from left hand grip assuming that for most, this was the non-dominant hand. It was measured using a Martin strain-gauge dynamometer which measures hand grip strength.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuotes: "The patients were randomly assigned to receive either magnesium-lactate-citrate tablets, 15 mmol daily (5 mmol 3 times daily) or matching placebo"; "Block randomization of eight was used"

Comment: The process of randomization is not described adequately. There was a statistically significant difference in age between participants in the treatment group and participants in the placebo group; the placebo group was younger.

Allocation concealment (selection bias)Unclear riskAuthors do not describe methods for allocation concealment

Blinding (performance bias and detection bias)
All outcomes
Unclear riskQuote: "We randomized 49 chronic alcoholics, moderate to heavy drinkers for at least 10 years to receive oral magnesium or placebo treatment for 6 weeks according to a double-blind protocol"

Comment: The study doesn't describe a blinding procedure adequately. It is therefore unclear whether the participants, providers or outcome assessors were blinded.

Incomplete outcome data (attrition bias)
All outcomes
High riskQuote: "There were three drop-outs, all from the placebo group. One died suddenly, and two were lost from follow-up. These subjects have been excluded in the statistical calculations"

Comment: None of the three drop-outs were accounted for and were all from the placebo group. This may have an impact on the results due to the small sample size.

Poikolainen 2008

MethodsRandomisation: placebo-controlled, parallel-group

Drop-outs in placebo group: 23/54

Drop-outs in treatment group: 37/64


ParticipantsN = 118 randomised

Recruitment Setting: outpatient clinic in Finland

(1) recruits had mild to moderate alcohol withdrawal symptoms or elevated GGT (men > 80 UI, women > 50 UI)


InterventionsTreatment: 10 mmol Mg carbonate-Mg acetate-Mg hydroxide tablet mixture BID for eight weeks

Control: matching placebo


OutcomesPrimary:

(1) GGT

Secondary:

(1) AST

(2) ALT

(3) Muscle strength, as measured by handgrip dynamometer

(4) Depressive symptoms, as assessed by 21-item Beck Depression Inventory


NotesExclusion criteria: participants with symptoms (i.e. alcohol-related psychosis) that required inpatient care; history of heart rhythm disturbances; contraindications against Mg treatment (i.e. heart failure, renal failure); abnormal serum creatinine

Muscle strength data: used data from left hand grip assuming that for most, this was the non-dominant hand. It was measured using a Martin strain-gauge dynamometer which measures hand grip strength.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: "Patients were randomized as individuals. Codes determining groups were derived from computer-generated random numbers"

Allocation concealment (selection bias)Unclear riskQuotes: "codes [were] applied with the help of sealed opaque envelopes"; "Code was kept secret by one of us (HA) and broken after the last patient had had his after-treatment examination"

Comment: It's unclear whether HA, who apparently knew the randomization code prior to assignment, was involved in assignment and enrolment

Blinding (performance bias and detection bias)
All outcomes
Unclear riskQuote: "Mg and placebo tablets were identical. Both groups were told of the possibility of mild diarrhoea as a side-effect"; "The effect of Mg was studied in a randomized, parallel group, double-blind trial"

Comment: The blinding procedure is not described adequately.

Incomplete outcome data (attrition bias)
All outcomes
High riskQuote: "in spite of their promise to attend, many subjects failed to keep their follow-up appointments. The follow-up examination was completed by 58 patients (49%)"

Comment: Data from authors' intention-to-treat analysis were not published. Authors were emailed for data in July 2012 but did not respond to our requests.

Wilson 1984

MethodsRandomisation: placebo-controlled, double-blinded, parallel-group

Drop-outs in placebo group: 4 participants not analysed

Drop-outs in treatment group: 5 participants not analysed

Note: Number of participants randomised to each treatment group not reported


ParticipantsN = 87 randomised; age range:16 - 65

Recruitment Setting: hospital-based chemical withdrawal unit in Canada


InterventionsTreatment: 16.24 mEq Mg sulphate IM q6h for 24 hours

Control: 0.9% NaCl IM solution

All participants received alcohol withdrawal protocol, consisting of routine orders for chlordiazepoxide (50 - 100 rng orally every 6 hours as required) and chlordiazepoxide (100 mg orally every 6 hours) for persistent withdrawal.


OutcomesMean of 3 x 7-point rating scales used to assess:

Diaphoresis
Tremor
Vomiting
Hallucinations
Overall severity of withdrawal.

Chart review used to assess:

Grand mal seizures
Delinum tremens
Amount of chlordiazepoxide
Change in systolic blood pressure
Change in diastolic blood pressure
Change in heart rate.


NotesExclusion criteria: history of renal insufficiency or cardiac arrhythmia.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: "the patient ... was then assigned to treatment with either magnesium sulfate or normal saline according to a table of random numbers"

Allocation concealment (selection bias)Unclear riskQuote: "the code was not broken until the study was completed"

Comment: Risk of allocation concealment is unclear.

Blinding (performance bias and detection bias)
All outcomes
Low riskQuote: "according to a double-blind protocol"; "Staff did not have access to the serum magnesium levels until the ratings were completed and the patient had been discharged." "The solutions were supplied in identical ampules"

Comment: Patients, intervention providers and outcome assessors probably blinded

Incomplete outcome data (attrition bias)
All outcomes
High risk"The small incidence of grand ma1 seizures and delirium tremens encountered in the present study did not lend itself to statistical analysis. Six of 100 patients in the study developed delirium tremens and three such patients were in each treatment group. Similarly, of five patients experiencing a total of six grand mal seizures (one patient in the magnesium sulfate group had two seizures), two were treated with magnesium sulfate and three with placebo"

Comment: The above participants were excluded from statistical analysis

As people were discharged, they were excluded from any analyses of serum magnesium. Sufficient participants were available for analysis up to 72 hours post-dose, however more than 20% were lost by 96 hours post-dose. Data from their intention-to-treat analysis were not published; authors did not respond to our request for missing data (email sent July 2012).

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Aagaard 2003Study participants were not randomised to a magnesium treatment group

Alexander 1978Study was not conducted in people with a current history of alcohol dependence

Avsaroglu 2005Study participants were not randomised to a magnesium treatment group

Bardhan 1988Study was not conducted in participants with a current history of alcohol dependence

Bjorneboe 1988Study participants were not randomised to a magnesium treatment group. Not a randomised controlled trial.

Bonkovsky 1991Magnesium was given to study participants in combination with other interventions

Coetzee 1998Study was not conducted in participants with a current history of alcohol dependence

Colson 1964Study was not conducted in participants with a current history of alcohol dependence

Crews 2001Study participants were not randomised to a magnesium treatment group

Deynet 1979Study participants were not randomised to a magnesium treatment group

Dols 1985Study was not conducted in people with a current history of alcohol dependence

Enmin 1969Study participants were not randomised to a magnesium treatment group

Fogarty 2006Study was not conducted in people with a current history of alcohol dependence

Gilleran 1996Study was not conducted in people with a current history of alcohol dependence

Gisselman 1982Patients were not at risk for acute withdrawal; all participants were abstinent for at least three months

Gisselman 1983Study was a duplicate of Gisselman 1982

Grove 1985Study was not conducted in people with a current history of alcohol dependence

Hantouche 1998Study was not conducted in people with a current history of alcohol dependence

Herpin 1996Study participants were not randomised to a magnesium treatment group

Herr 2000Study was not conducted in people with a current history of alcohol dependence

Hoes 1979Study participants were not randomised to a magnesium treatment group

Hoffmann 2004Study was not conducted in people with a current history of alcohol dependence

Hornyak 2004Not a randomised controlled trial

Hristova 1997Study participants were not randomised to a magnesium treatment group

Iber 1987Magnesium was given to study participants in combination with other interventions

Klag 1993Study participants were not randomised to a magnesium treatment group

Lee 2012Study was a retrospective chart review

Meyer 1977Study participants were not randomised to a magnesium treatment group

Monteiro 1997Study was not conducted in people with a current history of alcohol dependence

Mooney 1985Not a randomised controlled trial

Murck 1998Study was not conducted in people with a current history of alcohol dependence

Mussalo-Rauhamaa 1987Study participants were not randomised to a magnesium treatment group

Mutzell 1988Study participants were not randomised to a magnesium treatment group

Naderi-Heiden 2005Study was not conducted in people with a current history of alcohol dependence

Nowson 1989Study participants were not randomised to a magnesium treatment group

Paolisso 1989Study was not conducted in people with a current history of alcohol dependence

Pasternak 2005Study was not conducted in people with a current history of alcohol dependence

Pasternak 2006Study was not conducted in people with a current history of alcohol dependence

Pienaar 1995Study participants were not randomised to a magnesium treatment group

Princi 1997Study participants were not randomised to a magnesium treatment group

Prokop 1970Study was not conducted in people with a current history of alcohol dependence

Prokop 1971Not a randomised controlled trial

Pumarino 1996Study was not conducted in patients with a current history of alcohol dependence

Rissanen 1987Study participants were not randomised to a magnesium treatment group

Ritschel 1970Study was not conducted in people with a current history of alcohol dependence

Rouse 1983Study was not conducted in people with a current history of alcohol dependence

Schmidt 1994Study was not conducted in people with a current history of alcohol dependence

Schroder 2004Study was not conducted in people with a current history of alcohol dependence

Sherbaniuk 1985Study was not conducted in people with a current history of alcohol dependence

Simon 1988Study participants were not randomised to a magnesium treatment group

Singh 1996Study was not conducted in people with a current history of alcohol dependence

Sos 2004Study was not conducted in people with a current history of alcohol dependence

Stamler 1997Study participants were not randomised to a magnesium treatment group

Steyn 1986Study participants were not randomised to a magnesium treatment group

Ueshima 2004Study was not conducted in people with a current history of alcohol dependence

Wheeler 1983Study participants were not randomised to a magnesium treatment group

Zygmunt 2003Study was not conducted in people with a current history of alcohol dependence

 
Comparison 1. Magnesium versus placebo

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Muscle strength3226Std. Mean Difference (IV, Random, 95% CI)0.04 [-0.22, 0.30]

 
Summary of findings for the main comparison. Magnesium compared to placebo or standard care for symptoms of alcohol withdrawal syndrome

Magnesium compared to placebo or standard care for symptoms of alcohol withdrawal syndrome

Patient or population: people with symptoms of alcohol withdrawal syndrome
Settings: hospital
Intervention: magnesium
Comparison: placebo or standard care

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

Placebo or standard careMagnesium

muscle strength
dynamometer¹
Follow-up: 6 - 8 weeks
The mean muscle strength in the intervention groups was
0.04 standard deviations higher
(0.22 lower to 0.3 higher)
226
(3 studies)
⊕⊝⊝⊝
very low2,3,4
SMD 0.04 (-0.22 to 0.3)

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. 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;

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.

 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.
 
Table 1. Criteria for risk of bias in RCTs and CCTs

  

Item
 

Judgement
 

Description

1random sequence generation (selection bias)LowThe investigators describe a random component in the sequence generation process such as: random number table; computer random number generator; coin tossing; shuffling cards or envelopes; throwing dice; drawing of lots; minimization

  HighThe investigators describe a non-random component in the sequence generation process such as: odd or even date of birth; date (or day) of admission; hospital or clinic record number; alternation; judgement of the clinician; results of a laboratory test or a series of tests;  availability of the intervention

  UnclearInsufficient information about the sequence generation process to permit judgement of ‘Yes’ or ‘No’.

2 allocation concealment (selection bias)LowInvestigators enrolling participants could not foresee assignment because one of the following, or an equivalent method, was used to conceal allocation: central allocation (including telephone, web-based, and pharmacy-controlled, randomisation); sequentially numbered drug containers of identical appearance; sequentially numbered, opaque, sealed envelopes.

  HighInvestigators enrolling participants could possibly foresee assignments because one of the following method was used: open random allocation schedule (e.g. a list of random numbers); assignment envelopes without appropriate safeguards (e.g. if envelopes were unsealed or non ­opaque or not sequentially numbered); alternation or rotation; date of birth; case record number; any other explicitly unconcealed procedure.

  UnclearInsufficient information to permit judgement of ‘Yes’ or ‘No’. This is usually the case if the method of concealment is not described or not described in sufficient detail to allow a definite judgement

3blinding of patients, provider, outcome assessor

 
Low

 

 
Blinding of participants, providers and outcome assessor and unlikely that the blinding could have been broken;

Either participants or providers were not blinded, but outcome assessment was blinded and the non-blinding of others unlikely to introduce bias.

No blinding, but the objective  outcome measurement are not likely to be influenced by lack of blinding

  HighNo blinding or incomplete blinding, and the outcome or outcome measurement is likely to be influenced by lack of blinding;

Blinding of key study participants and personnel attempted, but likely that the blinding could have been broken;

Either participants or outcome assessor were not blinded, and the non-blinding of others likely to introduce bias

  UnclearInsufficient information to permit judgement of ‘Yes’ or ‘No’;

5incomplete outcome data

For all outcomes except retention in treatment or drop-out
Low

 

 

 
No missing outcome data;

Reasons for missing outcome data unlikely to be related to true outcome (for survival data, censoring unlikely to be introducing bias);

Missing outcome data balanced in numbers across intervention groups, with similar reasons for missing data across groups;

For dichotomous outcome data, the proportion of missing outcomes compared with observed event risk not enough to have a clinically relevant impact on the intervention effect estimate;

For continuous outcome data, plausible effect size (difference in means or standardized difference in means) among missing outcomes not enough to have a clinically relevant impact on observed effect size;

Missing data have been imputed using appropriate methods

All randomised patients are reported/analysed in the group they were allocated to by randomisation irrespective of non-compliance and co-interventions (intention to treat)

  HighReason for missing outcome data likely to be related to true outcome, with either imbalance in numbers or reasons for missing data across intervention groups;

For dichotomous outcome data, the proportion of missing outcomes compared with observed event risk enough to induce clinically relevant bias in intervention effect estimate;

For continuous outcome data, plausible effect size (difference in means or standardized difference in means) among missing outcomes enough to induce clinically relevant bias in observed effect size;

‘As-treated’ analysis done with substantial departure of the intervention received from that assigned at randomisation;

 

  UnclearInsufficient reporting of attrition/exclusions to permit judgement of ‘Yes’ or ‘No’ (e.g. number randomised not stated, no reasons for missing data provided; number of drop out not reported for each group);