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17 Articles in Volume 20, Issue #3
20/20 with Dr. Suzanne Amato Nesbit: Clinical Pharmacy Roles and Disparities
A Clinician’s Guide to Treating Chronic Overuse Injuries
Adhesive Arachnoiditis: No Longer a Rare Disease
Analgesics of the Future: Cebranopadol as an Opioid Alternative
Ask the PharmD: What role do vitamin D supplements play in treating dysmenorrhea?
Behavioral Pain Medicine: Managing the Affective Components of Pain
Chronic Fatigue Syndrome: Naltrexone as an Alternative Treatment
Chronic Pain and Coronavirus
Connecting the Dots: How Adverse Childhood Experiences Predispose to Chronic Pain
Editorial: Why Are ER Opioids Out of Favor?
Fibromyalgia as a Neuropathic Pain Disorder: The Link to Small Fiber Neuropathy
How the COVID-19 Pandemic Is Transforming Pain Care
Hydroxychloroquine Use and Risk in the Management of Systemic Lupus Erythematosus
Management of Trigeminal Neuralgia in Multiple Sclerosis
Optimizing Care Using a Trauma-Informed Approach
Pediatric Pain Management: A Review of Clinical Diagnosis and Management
The Use of Low Dose Naltrexone in the Management of Chronic Pain

Ask the PharmD: What role do vitamin D supplements play in treating dysmenorrhea?

Controlled trial results largely support the use of vitamin D for minimizing the use of other pain relief medications and reducing pain intensity from menstrual pain.
Pages 11-13

Dysmenorrhea, or menstrual pain, occurs in up to 90% of women and can have a detrimental effect on quality of life as symptoms become severe.1,2 Primary dysmenorrhea is characterized by pain without underlying pathology. Secondary dysmenorrhea refers to menses precipitated by an underlying pathology or a different medical condition. The most common cause of secondary dysmenorrhea in adolescence is endometriosis.2

Crampy, suprapubic pain reproducible from one menstrual cycle to another is the defining characteristic of primary dysmenorrhea. Painful uterine contractions are believed to be caused by a progesterone withdrawal at the beginning of menses. Uterine contractions lead to ischemia, resulting in pain that is presumably regulated by prostaglandins.1 In clinical studies, primary dysmenorrhea has been associated with high prostaglandin levels in menstrual fluid and high urinary leukotriene levels, supporting the theory that these inflammatory markers have a role in the pathophysiology of the disease.2

The differential diagnosis of primary dysmenorrhea is complex and multifactorial. Associated symptoms such as diarrhea, nausea, light-headedness, and fatigue could be indicative of any number of disorders (eg, ovarian cysts, pelvic adhesions, inflammatory bowel disease).1 Several symptoms warrant a more in-depth evaluation: worsening pain, abnormal uterine bleeding, pain unrelated to the menstrual cycle, and a lack of response to treatment should be investigated for a secondary etiology.2

Medical, complementary, and alternative therapies are all options for treating primary dysmenorrhea. Pharmacologic treatment begins with NSAIDs, due to their mechanistic interruption of prostaglandin production. NSAIDs are taken for approximately 5 days of every cycle, beginning 1 to 2 days before menses and discontinued after 2 to 3 days of bleeding. There is no preference among the class concerning safety or efficacy.2

Hormonal contraceptives may be considered as well; these indirectly decrease prostaglandin and leukotriene production by preventing endometrial proliferation, ovulation, or both. Several dosage forms have demonstrated efficacy. The decision to use one method over another should be patient-driven. Exercise, heat treatment, and several dietary supplements also exist as treatment options with limited supporting evidence.2

Current Recommendations on Vitamin D

The American College of Obstetricians and Gynecologists (ACOG) mentions vitamin D supplementation in their committee opinion on dysmenorrhea and endometriosis in the adolescent, but there is no recommendation for or against treatment.1 The majority of available literature is focused on vitamin D and primary dysmenorrhea. A clinical trial from 2012 investigated use of vitamin D supplementation for treating dysmenorrhea and found a significant reduction in the intensity of menstrual pain among participants randomized to a single high dose of oral vitamin D.3 One double-blind clinical trial investigated the effects of supplementation on endometriosis-related pain after surgical treatment with laparoscopy and found no significant reduction in dysmenorrhea and/or pelvic pain.4

The proposed mechanism of benefit for vitamin D is related to the metabolism of prostaglandins. (Image: iStock)

The two forms of vitamin D are ergocalciferol (D2) and cholecalciferol (D3). Ergocalciferol is derived from yeast; cholecalciferol from lanolin. At nutritional doses the two forms are equivalent, but cholecalciferol is more potent at large doses. Vitamin D is converted to 25-hydroxyvitamin D [25(OH)D] in the liver. A serum 25(OH)D level less than 20 ng/mL is considered inadequate, and a level less than 12 ng/mL can lead to rickets in infants and osteomalacia in adults.5

Vitamin D receptors can be found in several anatomical locations related to reproduction: receptors in the ovaries, uterus, placenta, and pituitary gland suggest a link between vitamin D and reproduction is probable.6 Whether vitamin D is a causative factor of dysmenorrhea or menstruation leads to deficiency of vitamin D has yet to be ascertained.7

The proposed mechanism of benefit for vitamin D is related to the metabolism of prostaglandins. Calcitriol, the endogenous active form of vitamin D, regulates the expression of genes involved in prostaglandin synthesis and catabolism. By repressing key prostaglandin synthesis enzymes and upregulating catabolism enzymes, the number of circulating prostaglandins will be minimized, and uterine pain will theoretically be reduced.8 There are several observational studies that assess the role of vitamin D in treating primary dysmenorrhea, but the most recent randomized trials provide the highest quality evidence and shape a recommendation for its use in clinical practice.

What the Literature Shows

Available literature consists of small international trials with conflicting results. Three studies have demonstrated a significant improvement in pain severity after vitamin D supplementation, measured by a visual analog scale (VAS). However, trial protocols were variable. In the 2012 clinical trial investigating the use of vitamin D supplementation for treating dysmenorrhea mentioned previously, 40 women age 18 to 40 with primary dysmenorrhea were randomized to a single oral loading dose of cholecalciferol (300,000 IU) or placebo 5 days before the beginning of their menstrual cycle.

Participants were included if they had menstrual cycles lasting 21 to 35 days, menstruation lasting 3 to 7 days, 4 consecutive painful periods in the last 6 months, and a serum 25(OH)D level below 45 ng/mL. NSAID use was permitted and recorded. The baseline VAS score was 5.6 in the placebo group and 5.9 in the treatment arm. At the end of the two-month study, there was a significant reduction in pain intensity in the vitamin D group in comparison to the placebo group. The mean (SD) change from baseline in the vitamin D treatment group was –2.3 (1.3) points on the VAS and only 0.05 (0.75) points in placebo. The greatest pain reduction was achieved in women with more severe baseline symptoms in the vitamin D group (r=-0.76, P<0.001). There was significantly more NSAID use in the placebo group.3

A 2016 trial evaluated the effect of vitamin D among a similar population of women, ages 18 to 30. Enrolled patients had a serum 25(OH)D level < 30 ng/mL. Severe vitamin D deficiency was defined as a serum level < 10 ng/mL (62% of study population), and moderate deficiency was 10 to 19 ng/mL (38% of population). Sixty participants were randomized to 50,000 IU of oral vitamin D weekly or placebo for 8 weeks. Among women in the treatment group, baseline pain was mild in 3 patients (13%), moderate in 16 (69.9%), and severe in 4 (17.4%). After supplementation, 22 patients (95.7%) had mild and 1 patient (4.3%) had moderate pain. Pain intensity was significantly reduced in the vitamin D group after 8 weeks of treatment and
1 month after the end of the study. The difference in pain intensity between groups was statistically significant at both assessments. A significant inverse correlation was discovered between serum vitamin D level and pain intensity at the end of 8 weeks (r=-0.69) and 1 month later (r=-0.76), P<0.001. NSAID use was also significantly lower with treatment at the end of the study and one-month follow-up.9

Another trial supporting the use of vitamin D for primary dysmenorrhea was conducted among 897 adolescent girls ages 12 to 18 years. The study population received 50,000 IU of oral vitamin D weekly for 9 weeks. Participants were placed into one of four cohorts: premenstrual syndrome (PMS) only, dysmenorrhea only, both PMS and dysmenorrhea, or healthy individuals. Pain intensity was assessed using a 5-point VAS. Participants were vitamin D deficient if their serum level was < 20 ng/ml (85.3% of participants), insufficient at 20-30 ng/mL (9.7%) and sufficient with a level > 30 ng/mL (4.9%).10

After 9 weeks of treatment, 63.5% of participants had sufficient levels of vitamin D (P<0.001) and the incidence of patients with dysmenorrhea and dysmenorrhea with PMS was significantly reduced (P<0.001). There was a significant reduction in pain intensity among the individuals with dysmenorrhea and the use of medications for pain relief was also significantly reduced.10

A clinical trial in opposition of vitamin D evaluated 85 students age 18 to 32 with moderate or severe primary dysmenorrhea. Study participants were randomized to 1000 mg calcium/5000 IU vitamin D daily, 1000 mg calcium daily, or placebo from the 15th day of their menstrual cycle until menstrual pain disappearance in the following cycle, for a duration of three cycles. Funding did not support the collection of serum 25(OH)D levels. The mean (SD) baseline pain intensity among all participants was 6.1 (1.6).11

Average pain intensity after treatment was significantly lower in the calcium group (-1.6, CI –2.6 to –0.6), but not the calcium/vitamin D group (-0.7, CI –1.6 to 0.3). This was the only trial that reported adverse events. Rates of constipation and headache were comparable between groups. It is important to note that this trial did not meet power.11

In terms of clinical conclusions, see the authors' list of practical takeaways above.

Last updated on: June 2, 2020
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