From Alternative Medicine Alert, March 2002
By Georges Ramalanjaona, MD, DSc, FACEP, MBA
Fibromyalgia (fm) is a common rheumatic disorder that affects mainly middle-aged women (mean age 40-50 years). The estimate of its prevalence in the general population ranges widely, from 0.75% to 10.5%, vs. 20% in an academic rheumatology center.(1) Although its cause has yet to be identified, the symptoms and signs of FM are well-defined and classified by the 1990 American College of Rheumatology (ACR) Criteria. This classification shows that FM can be differentiated from other rheumatic diseases with an 85% accuracy.(2) Symptomatic treatment of FM includes a combination of drugs, acupuncture, exercise, rest, and psychological support.(3-5)
Recent studies indicate that patients with FM display decreased magnesium (Mg) levels in leukocytes compared to control groups.(6) Abraham et al hypothesized that Mg deficiency found in muscle cells may play a role in the development of FM. The group demonstrated that a daily supplement of 300-600 mg of Mg malate resulted in improvements of symptoms as well as in the number and severity of tender points.(7) These findings were later supported by other authors.(8,9)
When treating patients with FM, there are two goals:
1. Adequately treating potentially reversible factors such as electrolyte imbalances or vitamin deficiency.
2. Identifying a subgroup of FM patients that might benefit from Mg supplementation. Most people with FM do not have low serum Mg levels, and serum levels do not reflect the levels of Mg in tissue.(10) However, many FM patients appear to suffer from Mg deficiency and it appears important to assess Mg levels in all patients for potential relief of their musculoskeletal symptoms.
Because vitamin B1 administration requires Mg supplementation, there is theoretical biochemical evidence that a combination of Mg and B1 would be more effective than either B1 or Mg alone in treating FM patients. However, there is no clinical data to prove this.
Mechanism of Action
Although the exact mechanism of action of Mg remains unknown, it is crucial in many functions in the body.
Mg is important for many metabolic functions in the human body. It activates almost all the enzymes of the glycolytic and Kreb’s cycle, which transform fat and sugar into high-energy phosphate (ATP). Low levels of ATP commonly are found in FM and may play a significant role in the genesis of FM symptoms.(11,12) Without Mg, ATP is broken down easily into ADP and inorganic phosphate, which are less efficient than ATP in generating energy for cell metabolism and transport.(12) This process is important in the brain, which stores 20% of total body ATP. A low level of Mg leads to a low level of ATP, which may cause a decline in cognitive function.
Both Mg and malic acid, a non-toxic organic dicarboxylic acid, are known to be involved in ATP synthesis under aerobic and hypoxic conditions, which is the basis of the combined use of malic acid and Mg in treatment of FM.(7,8)
Along with calcium, Mg is crucial for adequate muscle metabolism and function. In Mg deficiency, there is excessive muscle tension, which leads to muscle spasms, restlessness, tics, and twitches. Also, histochemical studies show that tender points in FM muscle are deficient in ATP. Nuclear magnetic resonance spectroscopy indicates abnormally high-energy phosphate metabolism in exercising FM muscle.(13)
Mg inhibits many nerve receptors such as 5HT3 or NMDA, which are related to the origin of certain types of FM pain.14 Additionally, Mg regulates the release of neurohormones such as adrenaline, which increases with the occurrence of stress-related events.(14,15)
Relatively few well-designed and clinically significant trials have studied the effectiveness and safety of Mg supplementation in the treatment of FM.(7,8)
Russell et al used a proprietary tablet “supermalic” (SM), which contains 200 mg of malic acid and 50 mg of Mg, in two sequential trials of 24 subjects. The first trial was a randomized, double-blind, placebo-controlled, crossover study for a two-month period (grade I evidence-based).(8) Patients were randomized to either a fixed dose (three tablets, twice daily) of supermalic or to a placebo for four weeks, followed by a two-week washout and crossover to another four-week treatment period. All clinical assessments were conducted by a single examiner.
In a subsequent six-month, open-label trial, the effects of escalating doses of supermalic were assessed before and after resumption of the drug.(8) The 24 patients took three tablets of supermalic twice daily and increased their dosage every 3-5 days until they experienced acceptable outcomes or related side effects for a six-month period. All three primary outcomes used in this trial had been validated in prior studies.(16) They included patient self-assessment of pain on a visual analog scale; the tender point index (TPI), which is the sum of individual tenderness severities at each of the 18 ACR tender points; and the tender point average, which is the mean value derived from dolorimeter reading at each of the tender points.
The results did not show any clear treatment effect attributable to supermalic in the blinded, fixed low-dose trial. However, the open-label trial with dose escalation and a longer duration of treatment showed a significant reduction in severity in all three primary outcomes.
In another randomized, placebo-controlled, open-label, crossover trial (grade I evidence-based), Abraham et al used a combination of Mg (300-600 mg) and malate (1,200-2,400 mg) in 15 patients during an eight-week period.(7)
Results showed a statistically significant clinical improvement (P < 0.001) in the treatment group vs. placebo as measured by two outcomes. TPI scores (± SE) of 19.6 ± 2.1 prior to treatment decreased to 8 ± 1.1 and 6.5 ± 0.74 at four and eight weeks, respectively, on the Mg-malate combination. Conversely, following an average of eight weeks on SM, six patients were switched to placebo for two weeks. Their TPI scores statistically significantly increased (P < 0.001) from 6.8 ± 0.75 to 21.5 ± 1.4. Subjective improvement of myalgia symptoms occurred within 48 hours of Mg supplementation in the Mg-malate group; symptoms worsened in the placebo group.
Side effects related to long-term exposure to Mg include headache, muscular pain (usually relieved by aspirin), and mild gastrointestinal symptoms.(8)
In short-term trials, the most common side effect is watery diarrhea, which usually is short-lived. In this case, patients should decrease their next dose by 50%.(7) Hypokalemia may occur, in which case, Mg should be discontinued.
Contraindications and Precautions
Exercise caution when recommending Mg with other medications that may impair Mg absorption, thus decreasing its effects. These drugs include allopurinol, tetracycline, digoxin, iron salts, penicillamine, and phenothiazines.
Mg supplementation is safe during pregnancy, but it should be started in consultation with and under the supervision of the patient’s obstetrician.
Unless it is severe, diarrhea that is not induced by Mg supplements is not a contraindication to Mg supplementation.
Patients with renal disease should avoid magnesium supplementation.
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In the United States, Mg is sold in various oral forms, such as Mg citrate, Mg aspartate, Mg carbonate, Mg sulfate, Mg gluconate, and Mg oxide, or in combination with malic acid (supermalic).
When choosing among these forms, one needs to know that the citrate form has the best absorption record and that the oxide form is the most poorly absorbed and cheapest form available. Also, Mg gluconate and sulfate are easy to digest and should be used if diarrhea has occurred with prior Mg supplementation.
Mg hydroxide at an oral dosage of 500 mg/d significantly increases muscle magnesium level and seems to have comparable bioavailability with other forms of Mg preparation (citrate, lactate, and chloride). Most of the clinical trials used Mg hydroxide or gluconate.
The standard dose of Mg in published clinical trials varies from 50 mg to 600 mg PO daily. It is used in combination with malic acid because of its preliminary, theoretical effect in the treatment of FM.
The Mg hydroxide form has a wide margin of safety and superior effectiveness when used in combination with other supplements, such as malate. An oral dosage of 500 mg/d significantly increases muscle Mg level, which appears to correlate well with symptoms of FM.(7)
Based on preliminary data, Mg appears to be effective against tender point pain when used at high doses and in combination with malic acid.
Based on currently available studies, Mg is a reasonable addition or an alternative to other known drug therapies in subgroups of FM patients that have low magnesium levels or receive high doses of B1.
In addition, based on short-term studies, Mg seems to be effective in relieving well-known symptoms of FM and safe with only minimal and infrequent side effects. Further clinical trials with long-term analyses need to be performed to confirm preliminary findings, conduct more extensive investigations, and determine long-term effects of Mg in FM.
A trial of Mg supplementation should be prescribed for FM patients who have low Mg levels or who have tender point pain. However, Mg cannot be recommended as sole drug therapy in primary FM patients and is not a cure for FM.
Dr. Ramalanjaona is Associate Chairman for Academic Affairs, Department of Emergency Medicine, Seton Hall University, School of Graduate Medical Educa- tion, South Orange, NJ; and Director of Research, Division of Emergency Medicine, St. Michael’s Hospital, Newark, NJ.
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