Literature Review and Commentary

by Alan R. Gaby, MD

Vitamin D for Juvenile Onset Systemic Lupus Erythematosus

Forty-five patients ( mean age, 19 years) with juvenile-onset systemic lupus erythematosus (SLE) were randomly assigned to receive, in double-blind fashion, 50,000 IU of vitamin D3 or placebo once a week for 24 weeks. Medications remained stable throughout the study. At the end of the treatment period, compared with placebo, vitamin D significantly decreased disease activity, as determined by the SLE Disease Activity Index (p = 0.01) and by the European Consensus Lupus Activity Measurement (p = 0.006).

Comment

: Serum concentrations of 25-hydroxyvitamin D (25[OH]D) have been found to be low in a high proportion of SLE patients. However, 25(OH)D levels decline in response to inflammation, and low 25(OH)D levels in patients with inflammatory diseases such as SLE may not necessarily indicate vitamin D deficiency. Nevertheless, the results of this study suggest that vitamin D supplementation is beneficial. In another double-blind trial, the proportion of SLE patients who had a disease flare was significantly lower among those who received 2,000 IU per day of vitamin D for 12 months than among those who received placebo (10% vs. 24%; p < 0.005). Vitamin D also significantly decreased the mean erythrocyte sedimentation rate compared with placebo. In that study, 2% of the patients receiving vitamin D developed hypercalcemia and 2% developed hypercalciuria; these side effects were not seen in the placebo group (Abou-Raya A et al. The effect of vitamin D supplementation on inflammatory and hemostatic markers and disease activity in patients with systemic lupus erythematosus: a randomized placebo-controlled trial. J Rheumatol. 2013;40:265–272.) Therefore, it would be prudent to monitor serum and urinary calcium levels periodically in SLE patients who are being treated with 2000 IU per day or more of vitamin D.

Lima GL et al. A randomized double-blind placebo-controlled trial of vitamin D supplementation in adolescents and young adults with juvenile-onset SLE: improvement in disease activity and fatigue scores. Arthritis Care Res. 2016;68:91–98.

Magnesium for Insomnia

Forty-six individuals (mean age, 65 years) with moderate or severe insomnia and a mean dietary magnesium intake of 194 mg per day were randomly assigned to receive, in double-blind fashion, 250 mg of magnesium (as magnesium oxide) twice a day or placebo for 8 weeks. Compared with placebo, magnesium significantly increased mean sleep time (p = 0.002) and sleep efficiency (p = 0.03) and significantly improved the mean score on the Insomnia Severity Index (p = 0.006). Compared with baseline, magnesium supplementation improved the mean Insomnia Severity Index by 14.4% (p < 0.001).

Comment

: Insomnia is one of the symptoms of magnesium deficiency. Dietary intake of magnesium is frequently less than the Recommended Dietary Allowance of 420 mg per day for men and 320 mg per day for women. For many people, dietary magnesium intake is less than the mean amount consumed in this study. Dietary magnesium tends to be particularly low in African Americans and young women. I have seen many patients with nonspecific symptoms such as fatigue, anxiety, and insomnia experience marked improvement simply by taking a magnesium supplement (usually 400 mg per day). Good food sources of magnesium include nuts, whole grains, legumes, leafy green vegetables, fish, meat, and dairy products. More than 80% of the magnesium is lost in the refining of whole wheat flour to white flour and brown rice to white rice. Some 50% to 75% of the magnesium is lost in the water when vegetables are boiled.

Abbasi B et al. The effect of magnesium supplementation on primary insomnia in elderly: a double-blind placebo-controlled clinical trial. J Res Med Sci. 2012;17:1161–1169.

Topical Vitamin B12 for Aphthous Ulcers

Forty-two patients with aphthous ulcers were randomly assigned to receive, in double-blind fashion, a topical ointment containing a glucocorticoid and vitamin B12 (250 µg/g according to a personal communication from the author) or placebo (topical glucocorticoid alone) 4 times per day for 2 days. After 2 days, compared with baseline, mean pain severity had improved by 94% in the vitamin B12 group and by 65% in the placebo group. At that time, mean pain severity was significantly lower in the vitamin B12 group than in the placebo group (p < 0.001).

Comment

: The results of this study suggest that topical application of vitamin B12, as an adjunct to a topical glucocorticoid, decreased pain in patients with aphthous ulcers. The mechanism of action is not known. Further research is needed to determine whether vitamin B12 alone (without a glucocorticoid) would be beneficial.

Liu HL, Chiu SC. The effectiveness of vitamin B12 for relieving pain in aphthous ulcers: a randomized, double-blind, placebo-controlled trial. Pain Manag Nurs. 2015;16:182–187.

N-Acetylcysteine for Tobacco Addiction

Thirty-four patients (mean age, 51 years) with therapy-resistant tobacco use disorder were randomly assigned to receive, in double-blind fashion, 1500 mg of N-acetylcysteine (NAC) twice a day (morning and evening) or placebo for 12 weeks. All patients received smoking-focused group behavioral therapy. The proportion of patients who quit smoking (defined as exhaled carbon monoxide concentration of less than 6 parts per million) was significantly higher in the NAC group than in the placebo group (47.1% vs. 21.4%; p < 0.01). In addition, compared with placebo, NAC significantly decreased the mean score on the Hamilton Depression Rating Scale.

Comment

: There is evidence that a subnormal concentration of glutamate in the nucleus accumbens region of the brain increases compulsive or addictive behaviors. Administration of NAC has been shown to increase glutamate concentrations in the nucleus accumbens. NAC has been used with some success in the treatment of cannabis addiction and gambling addiction. The results of the present study suggest that NAC, as an adjunct to behavioral therapy, may also help some individuals to quit smoking.

Prado E et al. N-acetylcysteine for therapy-resistant tobacco use disorder: a pilot study. Redox Rep. 2015;20:215–222.

Thiamine for Parkinson’s Disease

Fifty patients (mean age, 70.4 years) with Parkinson’s disease (mean disease duration, 7.3 years) received 100 mg of thiamine intramuscularly twice a week for 3 months to 2.3 years. Significant improvement was seen in both motor and nonmotor symptoms. The mean score on the Unified Parkinson’s Disease Rating Scale (parts I–IV) improved significantly by 53% within 3 months and remained stable thereafter. The mean motor score (Unified Parkinson’s Disease Rating Scale part III) improved significantly by 55%. Some patients with milder disease had complete clinical recovery. The mean Fatigue Severity Scale score in 6 patients who had fatigue at baseline improved significantly by 55%. The authors hypothesized that a dysfunction of thiamine-dependent metabolic processes could cause selective neural damage in the centers typically affected by Parkinson’s disease, and might be a fundamental molecular event provoking neurodegeneration. They also suggested that thiamine might have both restorative and neuroprotective action in Parkinson’s disease.

Comment

: It is certainly encouraging when a safe and inexpensive treatment is reported to produce substantial benefit in patients with a difficult-to-treat condition such as Parkinson’s disease. However, the results should be viewed with caution, since the study did not include a control group. Thiamine has been available for many decades, and it has been used in large doses (both orally and parenterally) to treat a wide range of conditions, including some neurological disorders. If thiamine is indeed an effective treatment for Parkinson’s disease, it would be surprising that no one has previously observed this effect. Although placebo-controlled trials are needed to confirm the present report, a therapeutic trial of thiamine would be reasonable for patients with Parkinson’s disease. Clinicians who try this treatment are encouraged to report their findings in the Townsend Letter or elsewhere.

Costantini A et al. Long-term treatment with high-dose thiamine in Parkinson disease: an open-label pilot study. J Altern Complement Med. 2015;21:740–747.

Vitamin C and Athletic Performance

Plasma vitamin C levels were measured in 100 healthy males (mean age, 22 years). Compared with the 10 subjects with the highest levels (Group B), the 10 subjects with the lowest levels (Group A) had a significantly lower mean VO2 max value during the performance of aerobic exercise to exhaustion. All subjects were then randomly assigned to receive, in double-blind fashion, 1,000 mg per day of vitamin C or placebo for 30 days. After a 60-day washout period, each person received the alternate treatment for an additional 30 days. At baseline, mean daily vitamin C intake was 33 mg in Group A and 166 mg in Group B. Compared with placebo, vitamin C supplementation increased VO2 max (p < 0.08) in Group A, whereas this value decreased nonsignificantly in Group B, such that the difference in VO2 max between groups was no longer significant.

Comment

: In this study, a substantial minority of healthy young males consumed less than the Recommended Dietary Allowance (RDA) for vitamin C of 90 mg per day. Low vitamin C intake was associated with worse aerobic capacity, and this reduced aerobic capacity was corrected by vitamin C supplementation. Thus, adequate vitamin C intake is essential for optimal athletic performance. It is not clear whether vitamin C supplementation would improve athletic performance in people whose diet meets the RDA for vitamin C.

Paschalis V et al. Low vitamin C values are linked with decreased physical performance and increased oxidative stress: reversal by vitamin C supplementation. Eur J Nutr. 2016;55:45–53.

Magnesium for Chronic Postherpetic Neuralgia

Thirty patients with severe, intractable postherpetic neuralgia were randomly assigned to receive intravenous magnesium sulfate (30 mg per kg of body weight) or ketamine (1 mg per kg of body weight) every other day for a total of 3 treatments. The patients were given the infusions over a period of 1 hour, after being sedated with midazolam. Two weeks after the last infusion, the mean decrease in pain (as determined by a visual analogue scale) was 40% with magnesium and 51% with ketamine (p = 0.4 for the difference in the change between groups). Seven of the 15 patients in the magnesium group and 10 of the 15 patients in the ketamine group had at least a 50% reduction in pain 2 weeks after the end of the treatment.

Comment

: Chronic postherpetic neuralgia is frequently refractory to treatment. The results of the present study suggest that intravenous magnesium can relieve pain in some patients with this condition. The beneficial effect persisted for at least 2 weeks after the treatment was discontinued. Ketamine is a drug used to start and maintain anesthesia and is also used in some cases to treat chronic pain. Side effects, sometimes severe, are relatively common in patients receiving this drug. While magnesium was somewhat less effective than ketamine, it is much less likely to cause adverse effects. Intravenous magnesium should therefore be considered as a treatment option for patients with chronic postherpetic neuralgia.

Kim YH et al. Is magnesium sulfate effective for pain in chronic postherpetic neuralgia patients comparing with ketamine infusion therapy? J Clin Anesth. 2015;27:296–300.

Adverse Effect of Intravenous Iron

Four patients developed severe and symptomatic hypophosphatemia after receiving intravenous iron (ferric carboxymaltose) for iron-deficiency anemia due to heavy menstrual bleeding. Three of the 4 patients had secondary hyperparathyroidism (due to vitamin D deficiency) or tertiary hyperparathyroidism (parathyroid hormone promotes urinary phosphorus excretion), but the other patient had no risk factors for abnormal phosphate homeostasis. Serum phosphate levels prior to intravenous iron administration were normal or near-normal in all cases. The nadir of serum phosphate typically occurs around 2 weeks after the start of intravenous iron administration, but the time course can be prolonged. In 1 of the 4 cases, hypophosphatemia persisted for up to 3 months.

Comment

: Intravenous administration of iron is becoming increasingly popular, because it is more effective and causes fewer gastrointestinal side effects than oral iron. In previous studies, intravenous administration of ferric carboxymaltose induced hypophosphatemia (generally asymptomatic and transient) in 70% of women with iron-deficiency anemia due to gynecological conditions and in 3.8% of patients with non-dialysis-dependent chronic kidney disease. The decrease in serum phosphorus induced by intravenous ferric carboxymaltose appears to be mediated by an increase in serum levels of fibroblast growth factor 23 (FGF23). Since patients with chronic kidney disease have impaired renal excretion of phosphate and upregulated levels of FGF23, a further increase in FGF23 levels would be expected to have only a minimal effect on their renal phosphate excretion. In contrast, individuals with normal renal function are more likely to have a substantial increase in urinary phosphate excretion in response to intravenous iron.

In the treatment of hypophosphatemia, intravenous and oral phosphate should be administered with caution, because they have the potential to cause hypocalcemia, arrhythmias, ectopic calcification, and acute phosphate nephropathy. It is recommended that serum creatinine and serum phosphate be measured prior to treatment with intravenous iron. In patients with good renal function and low or low-normal phosphate levels, the authors of this report recommend measuring serum phosphate again 2 weeks after starting intravenous iron.

Blazevic A et al. Severe hypophosphataemia after intravenous iron administration. Neth J Med. 2014;72:49–53.