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Continued from part 1.
Each patient periodically answered three identical self-assessment questionnaires, at baseline and one at each of the two follow-up visits. A questionnaire was given to a patient at each visit and she was asked to complete it on her own (no interviewer allowed) in the waiting room, prior to seeing the physician.
Each patient was asked to take two 1-gram soft gels of either NKO or omega-3 18:12 fish oil (fish oil containing 18% EPA and 12% DHA) once daily with meals during the first month of the trial. During the following two months, patients continued on a cyclic dose of two 1-gram soft gels eight days prior to and two days during menstruation. Study medication was given for three months, at which time patients were asked to record all analgesics consumed for menstrual pain. All patients were asked to follow a normal healthy diet consisting of 20-percent fat (less than 10-percent animal fat), 40-percent protein, and 40-percent carbohydrates. Patients were re-evaluated 45 and 90 days alter recruitment.
The treating physician, the patient, and the epidemiologist performing the analysis were blinded until the completion of data analysis. The study was performed according to current International Conference on Harmonization guidelines on Good Clinical Practice. Reasons for withdrawal and adverse events were reported immediately. No crossover was allowed.
The primary objective of the study was to evaluate the effectiveness of Neptune Krill Oil for the management of premenstrual syndrome and dysmenorrhea. The secondary objective was to compare the effectiveness of NKO for the management of premenstrual syndrome with that of omega-3 fish oil. The study hypotheses were that Neptune Krill Oil can significantly reduce the physical and emotional symptoms of premenstrual syndrome and be significantly more effective for the management of PMS symptoms than fish oil.
Primary outcome measures were based on the scores of a self-assessment questionnaire for PMS based on the American College of Obstetricians & Gynecologists diagnostic criteria for premenstrual syndrome ranging from 0 (no symptoms) to 10 (unbearable)) (37) and the difference in quantity of analgesic consumption for menstrual pain at baseline, 45-day, and 90-day visits. Secondary outcome measures were based on the overall treatment assessment, adverse event monitoring, and compliance checks.
Changes over time within the same group (intragroup differences) in the efficacy measures were assessed using the paired Student's t-test. Differences between the two groups, NKO versus fish oil (intergroup variance), with respect to the change in the efficacy measure were assessed with analysis of variance (ANOVA). The study was designed as a prospective, randomized, controlled. double-blind trial, with a 20-percent difference in the change in physical and emotional scores accepted as clinically significant, 90-percent power, and 5-percent significance. Seventy patients were enrolled in the study, randomly assigned to either the active (NKO) or the control (fish oil) group.
Results
Of the 70 patients enrolled, all patients completed the three-month study period. Of those, 36 were randomized to the active group and 34 to the control group. The mean (SD) age of the active group patients was 33([+ or -] 5) and that of the control group was 32([+ or -] 7).
As illustrated in Tables 2 and 3, the scores of the self-assessment questionnaire demonstrated a statistically significant difference within the NKO group after intervals of both 45 days (first menstrual cycle) and 90 days (second and third cycle) in both emotional and physical symptoms related to PMS. By contrast, within the fish oil group a statistically significant difference was attained after 45 days only with symptoms of weight gain and abdominal pain. Other related physical symptoms (breast tenderness, joint pain, swelling, and bloating) as well as emotional symptoms (feeling overwhelmed, stress, irritability, and depression) revealed no significant difference between baseline and 45-day follow-up visits. At the 90-day interval or third study visit of the fish oil group, significant differences were observed only with weight gain, abdominal pain, and swelling. All other physical and emotional symptoms revealed no significant difference between baseline and 90-day follow-up visit of patients in the control group.
The analysis of data showed the types of analgesics consumed most frequently by women in both groups were ibuprofen (68%), acetaminophen (28%), and acetylsalicylic acid (4%). Analysis of variance showed no significant difference between the two groups for daily analgesic consumption during PMS as well as during menstruation, prior to initiation of study medications. Tile reported mean consumption prior to initiation of the trial was the same for both study groups--1.2 g ibuprofen or 2.5 g acetaminophen. The number of pain relievers used for menstrual pain by women taking NKO was significantly reduced to a mean daily consumption of 0.9 g ibuprofen and 1.5 g acetaminophen, a decrease of 33 percent and 40 percent, respectively, during the first treatment cycle (recorded at the 45-day visit). The mean reported analgesic consumption during the following treatment cycle(s) in the NKO group at the 90-day visit was 0.6g ibuprofen (total decrease of 50%) or 1.0 g acetaminophen (total decrease of 50%) per day. Student's t-test analysis showed a significant intra-group reduction for daily analgesic usage comparing baseline vs. 45 vs. 90-day visit. Women in the fish oil group reported a similar decrease of 0.9 g ibuprofen and 1.65 g acetaminophen, a decrease of 33 and 34 percent, respectively, during the first treatment cycle. The analgesic use remained essentially constant during the second cycle, with reported daily quantities of 0.8 g ibuprofen and 1.48 g acetaminophen, a decrease of 33 and 41 percent, respectively. Student's t-test analysis showed an intra-group reduction for the fish oil group for daily analgesic usage comparing baseline to 45-day and 90-day visits. At the end of the entire study, the comparative analysis between groups illustrated that women taking NKO consumed significantly fewer pain relievers during the 10 days of treatment than women receiving fish oil.
Analysis of variance showed that NKO was statistically more effective than fish oil for the management of emotional symptoms (feeling overwhelmed, stress, irritability, and depression; breast tenderness ; and joint pain. There was no significant difference observed between NKO and fish oil for the management of weight gain, abdominal pain, and swelling.
No serious adverse events were reported during the duration of the trial. Three of the 36 women in the NKO group reported a reduction of the duration of the menstrual cycle by 3-7 days during the first month of treatment. This was no longer observed after the dose was reduced to 2 gel caps per day for 10 days per month. NKO group patients exhibited minor oiliness of the facial skin. Patients taking NKO did not experience any gastrointestinal difficulties such as regurgitation, while 64 percent of the women in the fish oil group complained of unpleasant reflux. On the contrary, the NKO subjects reported an increase of alertness, energy, and well-being.
Discussion
Premenstrual syndrome is a complex psychoneuroendocrine disorder characterized by a combination of physiological, psychological, and social symptoms. It is estimated that 85-97 percent of women of reproductive age experience some symptoms in the premenstrual phase of the cycle and 30-40 percent of these women will seek medical advice. (38) For 3-5 percent of women, symptoms are severe enough to significantly disrupt their everyday life.
Given the complexity in the cause and symptomatology of premenstrual syndrome, a vast array of treatments have been suggested. A metaanalysis performed by Wyatt et al (39) on the annual rates of diagnoses and prescribing patterns in premenstrual syndrome during the years 1993-1998 showed a yearly decrease in the number of prescriptions linked to PMS diagnoses. Simultaneously, the meta-analysis revealed a recent increase in popularity of alternative or natural remedies. (39) A survey of medical herbalists in 1998 showed PMS to be the second-most common condition treated with natural health products. (40)
Numerous studies have shown a beneficial effect of omega-3 fatty acids on menstrual pain. (41-43) This is consistent with the fact that menstrual pain and cramps are caused by inflammation mediated by omega-6 fatty acid-derived eicosanoids.
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