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DIAG 1a In adults and young people in acute alcohol withdrawal, what is the clinical efficacy and safety of, and patient satisfaction associated with, a) a symptom-triggered compared with a fixed-schedule benzodiazepine dose regime b) symptom triggered compared with loading-dose regime c) loading-dose compared with fixed-schedule regime

ReferenceStudy type
Evidence level
Number of patientsPatient characteristicsInterventionComparisonLength of follow-upOutcome measuresSource of funding
Aagaard NK, Andersen H, Vilstrup H et al. Magnesium supplementation and muscle function in patients with alcoholic liver disease: a randomized, placebo- controlled trial. Scand J Gastroenterol. 2005; 40(8):972–979. Ref ID: 999RCT 1+

Power analysis
N=59

Drop-outs N=17
Patients with alcoholic liver disease (N=30 liver biopsy and N=29 other)

Inclusion criteria: Mean alcohol consumption of at least 60 g daily for 5 years or more.

Exclusion criteria included: Encephalopathy, psychiatric or severe cardiopulmonary disturbances, insulin- dependent diabetes

Mean age 49 yrs
Magnesium Sulphate

N=18

30 mmol 2 × 8 hrs infusion

12.5 g magnesium Oxide
Placebo

N=24
End of treatment (6 weeks)Muscle strength Prothrombin time BilirubinThe Danish Biomembrane Centre, Novo Nordisk Research Foundation, Centre for Research in Growth and Regeneration
Effect
Baseline muscle magnesium
7.7 and 7.4 μmol/g w.w or the magnesium and placebo groups respectively

Alcoholic liver disease patients vs normal subjects
7.6 vs 8.5 (p<0.001)

Magnesium vs placebo
At the end of treatment, magnesium compared with placebo was associated with a significantly:
Lower prothrombin index (0.64 vs 0.81, p<0.05)

At the end of treatment, there were no significant difference for magnesium compared with placebo for:
Mid-arm muscle area (ns)
Albumin
Bilirubin

When comparing baseline with end of treatment (6 weeks) magnesium was associated with significantly:
Higher albumin (486 vs 547, p<0.05)
Higher prothrombin index (0.57 vs 0.64, p<0.05)
Lower bilirubin (38 vs 24, p<0.05)

When comparing baseline with end of treatment (6 weeks) magnesium supplementation showed no significant differences for:

When comparing baseline with end of treatment (6 weeks) placebo was associated with significantly:
Higher albumin (488 vs 581, p<0.001)
Higher prothrombin index (0.70 vs 0.81, p<0.01)
Lower bilirubin (58 vs 27, p<0.05)
Poikolainen K. Magnesium treatment in alcoholics: a randomized clinical trial. Substance Abuse Treatment, Prevention, & Policy. 2008; 3(1) Ref ID: 424RCT double blind 1+

Power analysis ITT and per protocol analysis
N=118

Drop-outs: 60/118 (51%)
Patients who had nearly completed outpatient treatment for alcohol withdrawal symptoms (mild to moderate). The study group represents patients who can be treated using conventional routine outpatient care.

Inclusion criteria: Admitted for acute alcohol withdrawal symptoms, elevated S-GGT (men > 80 women > 50), no more Mg treatment within the the past 2 months unless 250 mg tablets or less, age 20 to 64, no history of heart disturbance and normal creatinine. Fixed address required.

Baseline characteristics not reported
Magnesium 200 mg twice daily for 8 weeks

N=64

Tablets consisted of magnesium carbonate, acetate and hydroxide.
Placebo

N=54
S-GGT
S-AST
S-ALT
Serum Mg
Creatinine
Beck Depression
Inventory
Handgrip
Blood pressure
8 weeksPharma Nord & Finnish Foundation for Alcohol Studies
Effect
No baseline magnesium levels were reported

Magnesium (Mg) vs placebo
After eight weeks of treatment there were no significant differences between the Mg and placebo groups on:
S-GGT
S-AST
S-ALT
Serum Mg
Beck Depression Inventory
Handgrip
Blood pressure

Mg vs placebo (controlling for baseline serum Mg level, coffee consumption and the number of unused Mg tablets)
After eight weeks of treatment magnesium therapy compared to placebo was associated with significantly higher:
Serum Mg (p=0.002)

Mg vs placebo (controlling for age, body weight, baseline alcohol intake, subsequent change in alcohol intake and baseline S-AST)
After eight weeks of treatment magnesium therapy compared to placebo was associated with significantly lower:
After treatment S-AST (30.7 vs 37.6 U/I, p<0.05)
Gullestad L, Dolva LO, Soyland E et al. Oral magnesium supplementation improves metabolic variables and muscle strength in alcoholics. Alcoholism: Clinical & Experimental Research. 1992; 16(5):986–990. Ref ID: 60RCT double blind 1+

Power analysis No ITT
N=52

N=3 drop-outs
Patients with continuous or periodic heavy alcohol abuse of at least ten years duration. patients were recruited from outpatient clinics and patients admitted to hospital for alcohol withdrawal syndromes, alcohol intoxication and chronic pancreatitis.

Exclusion criteria: S-creatinine >150 μmol/liter, cardiac A—V conduction disturbances and prior magnesium supplementation

Patient population
Mg: Mean age 61 yrs, M:F 17:7, duration of alcohol 20 yrs, alcohol consumption in month prior to trial 113 g/day

Placebo: Mean age 53 yrs, M:F 15:10, duration of alcohol 16 yrs, alcohol consumption in month prior to trial 118 g/day

There were no baseline differences between the groups except for age (used as covariate in subsequent analysis)
Magnesium cirtrate The tablets 5 mmol three times daily

N=24

Avoid magnesium rich foods and minimise alcohol consumption
Placebo

N=25
Liver function
Hematology
Electrolytes
Muscle strength
Side effects
6 weeks (end of treatment)None reported
Effect
Baseline magnesium levels.
At baseline serum magnesium levels were 0.86 and 0.84 mmol/liter for the magnesium and placebo groups respectively.

Baseline vs end of treatment
Magnesium
When comparing baseline to end of treatment (6 weeks), magnesium supplementation was associated with a significant decrease for:
GGT (121 vs 72 U/liter, pp<0.05)
ASAT (39 vs 27 U/liter, p<0.05)
ALAT (32 vs 24 U/liter, p<0.05)
Sodium (137 vs 139 mmol/liter, p<0.05)
Calcium (2.32 vs 2.44 mmol/liter, p<0.05)
Phosphate (1.01 vs 1.13 mmol/liter, p<0.05)

When comparing baseline to end of treatment (6 weeks), there was no significant difference for magnesium supplementation on:
Phosphate (ns)
Bilirubin (ns)
Creatinine (ns)

Placebo
When comparing baseline to end of treatment (6 weeks), placebo was associated with a significant decrease for:
Bilirubin (22 vs 11 μ/liter, p<0.05)

When comparing baseline to end of treatment (6 weeks), there was no significant difference for placebo on:
GGT (ns)
ASAT (ns)
ALAT (ns)
Sodium (ns)
Calcium (ns)
Potassium (ns)
Phosphate (ns)
Creatinine (ns)

Magnesium vs placebo
After six weeks of treatment magnesium supplementation compared to placebo was associated with statistically:
Higher sodium values (139 vs 137 mmol/liter, p<0.05)
Higher potassium values (4.4 vs 4.2 mmol/liter, p<0.05)
Higher magnesium values (0.88 vs 0.79 mmol/liter, p<0.05)
Lower ASAT (27 vs 61 mmol/liter, p<0.05)
Lower ALAT (24 vs 39 mmol/liter, p<0.05)

After six weeks of treatment there was no significant different for magnesium supplementation compared to placebo on:
GGT (ns)
Calcium (ns)
Phosphate (ns)
Creatinine (ns)
Bilirubin (ns)

Muscle strength
When comparing baseline with end of treatment, magnesium but not placebo was associated with an increase in muscle strength
Right hand (54 vs 62 bar, p<0.05)
Left hand (52 vs 57 bar, p<0.05)

Side effects
Magnesium supplementation was well tolerated with few side effects
Magnesium compared to placebo improved the general feeling of well being and reduced fatigue (42 vs 16%)

N=3 patients on magnesium reported mild diarrhea
Wilson A, Vulcano B. A double-blind, placebo- controlled trial of magnesium sulfate in the ethanol withdrawal syndrome. Alcoholism: Clinical & Experimental Research. 1984; 8(6):542–545. Ref ID: 110RCT double blind 1+N=100Patients admitted to a chemical withdrawal unit

Inclusion criteria: 6 to 65 yrs. No previous history of renal insufficiency or cardiac arrhythmia

Mean age 45.2 yrs. 21% female
2g i.m magnesium every 6 hrs for 24 hrs

N=50

Withdrawal protocol
Chlordiazepoxide 100 mg orally every 6 hrs

Plus

Chlordiazepoxide 50 to 100 mg every 6 hrs as required

Tapered at a rate of 100 mg/ 24 hrs
Placebo Withdrawal protocol as for intervention

N=50
Serum magnesium
Diaphoresis
Tremor
Vomiting
Hallucinations
Overall severity of withdrawal
Grand mal seizures
Delirium tremens
Amount of chlorodiazepoxide
Change in diastolic and systolic blood pressure (ns)
Change in heart rate
Until dischargeNone reported
Effect
At baseline, serum magnesium magnesium levels were o.75 and 0.80 mMol/L for the magnesium and placebo groups respectively.

Magnesium vs placebo
Patients given magnesium compared to those given placebo showed a significant increase in serum magnesium levels at 24 hrs (1.15 vs 0.80 approx, p<0.05) and 48 hrs (0.90 vs 0.80, p<0.05). There were no significant differences at baseline, 72, 96 and 120 hrs (ns).

The data were analysed in two different ways. Firstly, to see if magnesium supplementation should be administered to patients in acute alcohol withdrawal irrespective of serum level of admission. Secondly, if it should be administered to only those patients who are hypomagensic. For both types of analyses there were no significant differences in between the patients treated with magnesium and placebo for:
Diaphoresis (ns)
Tremor (ns)
Vomiting (ns)
Hallucinations (ns)
Overall severity of withdrawal (ns)
Amount of chlorodiazepoxide (ns)
Change in diastolic and systolic blood pressure (ns)
Change in heart rate (ns)

Delirium tremens (N=6, 3 patients in each group)
Seizure ((N=6 seziures (5 patients), 3 in magnesium group and 2 in placebo)

From: Evidence Tables

Cover of Alcohol Use Disorders
Alcohol Use Disorders: Diagnosis and Clinical Management of Alcohol-Related Physical Complications [Internet].
NICE Clinical Guidelines, No. 100.
National Clinical Guideline Centre (UK).
Copyright © 2010, National Clinical Guidelines Centre.

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