“To our knowledge, this is the first study investigating the effect of a single high dose of vitamin D in primary dysmenorrhea,” wrote the study authors, led by Antonino Lasco, MD, from the Department of Internal Medicine, University of Messina, Italy.
“Our data support the use of cholecalciferol in these patients, especially when exhibiting low plasmatic levels of 25(OH)D [25-hydroxyvitamin D],” they write.
The study is published February 27 in the Archives of Internal Medicine.
Pain trigger
Dysmenorrhea affects almost one half of menstruating women. The pelvic pain is believed to be triggered by excessive uterine production of prostaglandins, synthesized from omega-6 fatty acids before menses, that control vasoconstriction and uterine contractions.
According to the study authors, vitamin D may act as an anti-inflammatory and may regulate the expression of key genes involved in the prostaglandin pathway, causing decreased biological activity of prostaglandins.
The study included 40 women aged 18 to 40 years who had experienced at least 4 consecutive painful menstrual periods in the past 6 months and had a 25(OH)D serum level below the upper limit of the lowest quartile (<45 ng/mL). They were not taking calcium, vitamin D, oral contraceptives, or other medications, and they had not used an intrauterine contraceptive device during the previous 6 months.
The participants could use other means of birth control, however. They were also allowed to use nonsteroidal anti-inflammatory drugs (NSAIDs) as needed, but they had to record their use of these agents.
The women were randomly assigned to receive a single oral dose of 300,000 IUs of vitamin D (cholecalciferol) or placebo 5 days before the time they expected to begin their next menstrual period.
The primary outcome was intensity of menstrual pain as measured by a visual analog scale. The secondary outcome was use of NSAIDs.
After 2 months, baseline pain scores decreased 41% among women in the vitamin D group; there was no difference in scores among women taking placebo (P < .001). The greatest reduction in pain was among women in the vitamin D group who had the most severe pain at baseline (r = -0.76; P < .001)
During the study, none of the women in the vitamin D group needed NSAIDs to manage pain at 1 and 2 months, whereas 40% of those taking placebo used an NSAID at least once (P = .003).
Implications for chronic pain?
In an accompanying commentary, Elizabeth R. Bertone-Johnson, ScD, from the Division of Biostatistics and Epidemiology, University of Massachusetts, Amherst, and JoAnn E Manson, MD, from the Division of Preventive Medicine, Department of Epidemiology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, said the study provides support for larger randomized trials of vitamin D for treating pain-related conditions in women.
Chronic widespread pain and fibromyalgia syndromes are more prevalent in women, "likely owing to the influence of sex steroid hormones," they write.
This future research, they write, must address several key issues.
"First, it is important to know how long reductions in pain associated with a single high-dose vitamin D therapy would persist and how often treatment would need to be repeated," the editorialists write. They point out that each dose would need to be effective for a lengthy period for average daily intake to remain below recommended upper limits.
Because many women will experience dysmenorrhea for several years until menopause, follow-up of participants in vitamin D trials must be extended to better evaluate adverse effects and to compare risks and benefits, they note.
The editorialists also note that it remains unknown whether vitamin D would improve dysmenorrhea pain in women with higher 25(OH)D levels.
"If these findings are confirmed in future randomized trials, vitamin D supplementation may become an important new treatment option for women who experience menstrual pain disorders," they conclude. "In the meantime, encouraging all women to obtain the recommended dietary allowance for vitamin D (≥600 IU/d for women of reproductive age), as well as screening for low serum 25(OH)D levels among women with other risk factors for vitamin D deficiency, would be a rational interim approach."
Pain site
Approached for comment, Clifford Lo, MD, PhD, Director, Harvard Human Nutrition Program, and Medical Education Coordinator, Harvard Medical School Division of Nutrition, said that although the numbers were small, there was a convincing difference between the placebo and vitamin D groups in the study.
However, although it is plausible that vitamin D affects prostaglandins, the study did not specify which prostaglandin or which pain site might be involved, said Dr. Lo, whose research interests include vitamin D metabolism.
The study proposes an interesting possible mechanism, "but that's certainly not good enough for me to say that this is a good treatment for pain," said Dr. Lo. "It's very premature to say it's something we should use."
Pain associated with dysmenorrhea is generally subjective and not easily measured, he added. It is difficult to make conclusions about the effect an agent will have on pain when there is "no convincing biomarker" for the pain, as was the case with this study, said Dr. Lo.
The 300,000 IU dose of vitamin D used in the study is probably harmless if taken every month or 2, and even perhaps every week, but it could cause hypercalcemia if taken daily, said Dr. Lo. The typical vitamin D dose is 400 to 1000 IU/day.
Dr. Lo pointed out that because the participants in the study had vitamin D levels below 45 ng/mL, they were not exactly deficient in vitamin D to begin with. "Most people would say that you're not deficient until you're below 20 ng/ml," he said. "I would say that half the American population is below 30 ng/mL."
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