Friday, March 2, 2012

Vitamin D Relieves Menstrual Pain

Vitamin D Primary dysmenorrhea (menstrual pain) affects nearly half of menstruating women and is characterized by painful uterine cramping and other uncomfortable symptoms that may be debilitating in some cases. Now, a new study reports that a single high dose of vitamin D3 may significantly relieve the pain, without the need for other pain medications, for up to 2 months.

Writing in the February 27, 2012 edition of Archives of Internal Medicine, Antonino Lasco, MD, from the Department of Internal Medicine, University of Messina, Italy, and colleagues describe a randomized, double-blind, placebo-controlled trial of vitamin D3 for primary dysmenorrhea. The researchers enrolled 40 women to receive either a single oral dose of 300,000 IU vitamin D3 (cholecalciferol, N=20) or placebo (N=20), given 5 days prior to the expected start of their next menstrual period. The primary outcome was intensity of menstrual pain as measured on a visual analog scale; the secondary outcome was concurrent NSAID use for pain relief.

The women were 18 to 40 years of age and had experienced at least 4 consecutive painful periods during the prior 6 months, with pain starting one day before or on the day of menstrual flow. 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. All had vitamin D levels, measured as the 25(OH)D metabolite, within the lowest quartile of the normally expected range (mean, SD ≈ 28.5, 7.55 ng/mL). There was a significant correlation at baseline of lower 25(OH)D level and greater pain. Treatment and placebo groups were well balanced at baseline in terms of age, body mass index, severity of pain, and 25(OH)D levels.

At the 1-month and 2-month followup points, mean pain scores had decreased by 37% and 41%, respectively, from baseline levels among women assigned to vitamin D3 treatment (P<0.001), while only 3% and 2% average improvements at the two time points were observed among women assigned to placebo (P=NS). The greatest benefits were observed among women reporting the highest pain scores at baseline. Furthermore, women who took vitamin D3 reported no use of NSAIDs to manage pain during the 1- and 2-month followup points, while 40% of women assigned to placebo reported using the analgesics at least once (P=0.003).

Therefore, the authors conclude that vitamin D3 supplementation may be helpful in women experiencing dysmenorrhea, especially in those with lower 25(OH)D levels and greater pain. An added benefit is the avoidance or limiting of NSAID use to relieve the discomfort.

COMMENTARY: This is a pioneering study in the use of vitamin D3 for dysmenorrhea, and it may be a useful and economical option for many women. It should be noted that the average pain at baseline across both groups was moderate (mean ≈ 5.70). The large effect size for pain improvement with vitamin D3 [Cohen’s d ≈ 1.50, calculated by us, not the report authors] and the NSAID-sparing effect seem clinically important, but may have been distorted by small sample sizes. Much larger trials, with longer followup, would be helpful in confirming the results and the external validity of vitamin D as a worthwhile therapy for dysmenorrhea.

In an accompanying commentary, Elizabeth R. Bertone-Johnson, ScD, from the University of Massachusetts and JoAnn E Manson, MD, from Harvard Medical School, note that “the main source of pelvic pain in dysmenorrhea is believed to be prostaglandins synthesized from omega-6 fatty acids prior to menses, which control vasoconstriction and uterine contraction. Though nonsteroidal anti-inflammatory drugs (NSAIDs) and oral contraceptives are effective at managing the pain in many patients, these medications are not without risks” [Bertone-Johnson and Manson 2012].

They further observe that, while vitamin D for dysmenorrhea has not been previously evaluated, some studies have suggested its benefits in other menstrual and pain-related conditions in women, including premenstrual syndrome (PMS), endometriosis, and fibromyalgia. Beneficial mechanisms of vitamin D may be multifaceted: In the endometrium, the active metabolite — 1,25-dihydroxyvitamin D, or 1,25(OH)2D — decreases prostaglandin synthesis and increases prostaglandin inactivation, while also down-regulating prostaglandin receptor expression. This metabolite of vitamin D also may exert anti-inflammatory effects through other pathways.

In this small RCT by Lasco et al. a single, 300,000 IU dose of D3 had beneficial results extending to 2 menstrual periods (2 months), but it is not known if the effects might have persisted longer; nor do we know by how much 25(OH)D levels were increased in the treated patients. Bertone-Johnson and Manson express some concern about how often vitamin D therapy might need to be repeated; if it is every 2 months, this would equate with approximately 5,000 IU/day, which might be necessary for many years, so longer-term followup is needed to evaluate the safety of such doses over time.

Another consideration they raise is the baseline level of 25(OH)D at which supplementation might be most beneficial. Women in the Lasco et al. trial were not highly deficient, on average, so it remains unknown whether patients with much lower or higher serum levels of the vitamin at baseline also would respond as favorably.

Finally, we must question why a single, 300,000 IU vitamin D3 megadose once every two months would be preferred over more moderate daily supplementation, such as 4,000 to 5,000 IU D3/day. As we noted in a prior UPDATE [here], vitamin D is normally available in megadoses only by prescription as D2 (ergocalciferol) and this form is considered by many experts as inferior to D3. Furthermore, smaller but daily doses are more consistent with human physiology, which is attuned to moderate amounts of vitamin D3 gained during regular exposure of the skin to UVB rays in sunshine. So, hopefully, future trials of D3 for menstrual pain and other disorders will examine smaller daily-dose supplements that are readily available to patients from many pharmacies and other outlets, and at reasonable cost.

> Bertone-Johnson ER, JE Manson. Vitamin D for Menstrual and Pain-Related Disorders in Women: Comment on "Improvement of Primary Dysmenorrhea Caused by a Single Oral Dose of Vitamin D." Arch Intern Med. 2012;172(4):367-369 [
> Lasco A, Catalano A, Benvenga S. Improvement of Primary Dysmenorrhea Caused by a Single Oral Dose of Vitamin D: Results of a Randomized, Double-blind, Placebo-Controlled Study. Arch Intern Med. 2012;172(4):366-367 [

For a listing of other UPDATES discussing vitamin D for pain [click here].
For background research papers and a patient brochure [click here].

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