Complementary Therapies in Medicine (2011) 19, 187—193 available at www.sciencedirect.com journal homepage: www.elsevierhealth.com/journals/ctim A multicenter, randomized, double-blind, placebo-controlled trial evaluating the efficacy and safety of a far infrared-emitting sericite belt in patients with primary dysmenorrhea Chae Hyeong Lee a, Ju-Won Roh a, Chi-Yeon Lim b, Jin Hwa Hong c, Jae Kwan Lee c, Eung Gi Min a,∗ a Department of Obstetrics and Gynecology, Dongguk University Ilsan Hospital, College of Medicine, Dongguk University, 814 Siksa-dong, Goyang, Gyeonggi-do 410-773, Republic of Korea b Department of Medicine, Graduate School, Dongguk University, Seoul, Republic of Korea c Department of Obstetrics and Gynecology, Korea University College of Medicine, Seoul, Republic of Korea Available online 16 July 2011 KEYWORDS Far infrared ray; Primary dysmenorrhea; Randomized controlled trial; Sericite belt ∗ Summary Objective: To determine the efficacy and safety of a sericite which emits far infrared rays in the management of primary dysmenorrhea. Design: A multicenter randomized double-blind placebo-controlled trial. Setting: One hundred four patients with primary dysmenorrhea were randomized to wear a sericite or placebo belt during sleep for 3 menstrual cycles, and followed for 2 menstrual cycles. Hot packs were used to heat the ceramics and ensure slight pain relief in both groups. Main outcome measures: The main outcome measures were the severity of dysmenorrhea assessed by a 10-point visual analog scale (VAS) and the number of patients who took analgesics at each menstrual cycle. Safety was evaluated by physical examination and self-reporting of adverse events. Results: The baseline VAS scores were 7.27 ± 0.19 in the experimental group and 7.38 ± 0.19 in the control group. The severity of dysmenorrhea gradually decreased during the treatment period in both groups, with major improvements observed in the third treatment cycle (4.96 ± 0.30 in the experimental group and 5.69 ± 0.30 in the control group, p = 0.087). During the follow-up period, the decreased VAS score was maintained in the experimental group, whereas the VAS score gradually returned to baseline in the control group, which resulted in significant difference between the groups (5.08 ± 0.31 vs. 6.47 ± 0.31 at cycle 5, difference −1.39 [95% CI, −2.25 to −0.53], p = 0.0017). The number of patients who took analgesics decreased in both groups, but the differences were not statistically significant. No serious adverse events related to wearing the sericite belt occurred. Corresponding author. Tel.: +82 31 961 7360; fax: +82 31 961 7155. E-mail address: [email protected] (E.G. Min). 0965-2299/$ — see front matter © 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.ctim.2011.06.004 188 C.H. Lee et al. Conclusions: Our data suggest that a far infrared-emitting sericite belt with a hot pack might be used as an effective and safe non-pharmacologic treatment option for women with primary dysmenorrhea, with a prolonged effect after treatment. © 2011 Elsevier Ltd. All rights reserved. Introduction Primary dysmenorrhea is defined as cramping pain in the lower abdomen, occurring at the onset of menstruation, in the absence of any identifiable pelvic disease. Menstrual cramp is most severe during the first or second day of menstruation and typically lasts for 8—72 h, and may be accompanied by nausea, vomiting, fatigue, back pain, headaches, dizziness, and diarrhea.1 Dysmenorrhea is a common disorder in women of reproductive age, with an estimated prevalence of 18—81%.2 About 5—14% of patients with dysmenorrhea experience severe pain sufficient to cause disturbances in daily activities and absenteeism from work or school.3 Increased production of prostaglandins (PGs), especially PGF2␣, by the endometrium and myometrium during menstruation plays an important role in the pathogenesis of dysmenorrhea.4,5 PGF2␣ causes potent vasoconstriction of the uterine blood vessels and myometrial contractions, both of which reduce blood supply to the uterus.6 The resultant uterine muscle ischemia and hypoxia are thought to be the origin of pain in patients with primary dysmenorrhea.7 Non-steroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen and naproxen sodium, and oral contraceptives (OCs) are therefore the most common and rational choices for the treatment of primary dysmenorrhea. NSAIDs suppress endometrial PG biosynthesis by directly inhibiting cyclooxygenase activity. OCs reduce endometrial thickness, which leads to a reduction in PG release.8 However, 20—30% of the patients with primary dysmenorrhea either do not respond or obtain insufficient relief with these medications.7,9 Moreover, both treatments only have temporary effects and are associated with some adverse events. NSAIDs are associated with gastrointestinal upset or bleeding and serious kidney or liver failure. OCs are associated with nausea, headache, water retention, and vaginal bleeding and may cause venous thromboembolism and cervical cancer with prolonged use. Therefore, it is highly desirable to search for effective nonpharmacologic alternatives that can be easily used for the treatment of primary dysmenorrhea. Sericite is a petrographic term used to indicate highly refractive and fine-grained mica, usually muscovite in composition, found in hydrothermally altered rocks.10 Traditionally, sericite has been used in alleviating pain in the reproductive organs of Korean women.11 Since the properties of far infrared (FIR) rays emitted from sericite ceramics are known, they have been used in the medical field to promote health. We have numerous reports that beds made from sericite ceramics help relieve dysmenorrheic pain. FIR is an invisible electromagnetic wave with a longer wavelength than visible light. FIR is part of infrared radiation, which is subdivided into three categories according to different wavelengths, as follows: near (0.8—1.5 m), middle (1.5—5.6 m), and far (5.6—1000 m) infrared radiation.12 Thermal therapy using FIR has been widely applied in medicine, including the treatment of chronic fatigue syndrome,13 chronic pain,14 and wound healing.12 FIR can penetrate human skin up to several centimeters to exert its thermal effect.15,16 FIR might be useful in reversing the reduced uterine blood flow through the vasodilating effect in women with dysmenorrhea. Recently, it has been reported in Korea that underwear emitting FIR rays was effective in reducing the severity of dysmenorrhea. The epidemiologic importance of primary dysmenorrhea and the need for a safe, alternative strategy for the treatment of dysmenorrhea prompted us to investigate the efficacy of FIR in patients with primary dysmenorrhea. The aim of the present study was to assess the efficacy of FIRemitting sericite belt in the improvement of dysmenorrhea and in the reduction of analgesic use. Other outcome of interest was safety evaluation. Materials and methods This multicenter, randomized, double-blind, placebocontrolled study was conducted at 2 hospitals in Korea between August 2008 and September 2009. The study was conducted in accordance with Good Clinical Practice, guidelines of the International Conference on Harmonisation, and the Declaration of Helsinki. The study protocol was approved by an Institutional Review Board at each clinical research center. All patients provided written informed consent before enrollment. Study population Participants were recruited from the outpatient gynecological clinics in two university-based hospitals (Dongguk University Ilsan Hospital and Korea University Guro Hospital) and through poster advertising placed in public areas of the hospitals. Patients were first interviewed and screened by gynecologists to determine eligibility for this study. Patients filled out a questionnaire that asked about demographic characteristics, menstrual history, and medical and reproductive histories, and underwent screening procedures which included vital signs (blood pressure, pulse, respiration, and temperature), laboratory tests (complete blood count, hepatic and renal function tests, serum electrolytes, urinalysis, urine hCG, and CA125), and gynecologic examinations (Papanicolaou smear, bimanual examination, and pelvic ultrasonography) to rule out secondary dysmenorrhea. Magnetic resonance imaging was performed if judged clinically necessary. Patients were asked to place a mark on the 10-cm line at a point that corresponded to the level of pain intensity they felt. The visual analog scale (VAS) consists of a 10-cm horizontal scale with the descriptors ‘‘no pain at all’’ on the left and ‘‘the worst pain imaginable’’ on the right. The distance in centimeters from the low end of the VAS to the patient’s mark was used as a numerical index for the severity of pain. Efficacy and safety of sericite belt in women with primary dysmenorrhea 189 Patients meeting the following inclusion criteria were eligible for enrollment: women between 15 and 45 years of age; good health (determined based on medical history and physical examination); regular menstrual cycles (28 ± 7 days); pain score of ≥5 on a visual analog scale (VAS); and required analgesic medication for at least 4 of 6 menstrual cycles. Patients were excluded if they met any of the following criteria: oral contraceptives use within 6 months before the start of the study; wearing an intrauterine contraceptive device; diagnosed with or suspected to have pelvic disease such as endometriosis, adenomyosis, uterine myoma, ovarian tumor, endometrial polyp, pelvic inflammatory disease, and anomalies of the genital tract; pregnant or breastfeeding; pelvic surgery ≥2 times; and incomplete menstrual diary during the pre-treatment baseline period. Study design The study was conducted over 7 menstrual cycles as follows: (A) pre-treatment baseline period for 2 menstrual cycles; (B) treatment period (cycles 1—3); and (C) post-treatment follow-up period (cycles 4 and 5). Before starting treatment, all patients were observed for 2 menstrual cycles. The participants were then randomly assigned into one of the two groups (an experimental group treated with a sericite belt and a control group given a placebo belt) at the data coordinating center. The randomization sequence was computer-generated using a block size of 6, as a 1:1 allocation ratio to each treatment group with stratification for the study center. The belts were labeled with the randomization code and investigators, patients, and study statisticians were blinded to the treatment allocation. Patients were asked to wear the belt while sleeping at night for 3 consecutive menstrual cycles, after which patients were followed up for 2 menstrual cycles without wearing the belt. Patients were given a menstrual diary to record pain assessment using the VAS beginning 2 days before the onset of menses to the 4th day of menses, which was returned to the trained study personnel within 7 days after each menstrual period. Patients were allowed to take the medications that they usually used for pain relief and instructed to record the name and dose of the medication in the menstrual diary throughout the study period. The use of other complementary therapies for dysmenorrhea was not permitted during the study. Any adverse event was recorded, including the severity, duration, and outcome. Sericite belt and placebo belt The sericite and placebo belts were manufactured as two indistinguishable belts and designed to be comfortably secured to the lower abdomen using an elastic band and Velcro tape. The sericite produced at Gumcheon mines in Korea was used in this study. Natural sericite powder was baked at 1300 ◦ C to create ceramics after several phases of a purification process. The FIR emissivity and emission energy of sericite ceramics were measured using Fourier transform infrared spectrometer (Midac, Inc., Irvine, CA; Model M2400 Series) at the Korea Conformity Laboratories and the Korea Institute of Ceramic Engineering and Technology. The sericite ceramics emit FIR with a peak wave- Figure 1 Elastic belt with button-shaped sericite ceramics attached and a pocket behind them to keep a hot pack. length of 5—20 m when warmed to a temperature of 40 ◦ C. As compared with black body, the value of emissivity of sericite ceramics was 0.923 and the emission energy was 3.72 × 102 W/m2 . Forty-nine button-shaped sericite ceramics were attached to the belt individually using strings (Fig. 1). For the placebo belt, we used calcium carbonate, so-called stone powder, instead of sericite. A pouch over the ceramics in the belt was made to keep a hot pack. We used 9 × 7 cm sized disposable hot pack containing iron powder and other chemicals. Hot pack produces heat through oxidation process when it is exposed to air. It quickly heats up to 50 ◦ C and stays at that temperature for approximately 10 h. We included hot pack as a treatment in both groups to heat the ceramics and to conform with the requirements of the Ethics Committee to ensure slight pain relief during treatment. Outcome measures The primary outcome parameter was the change in maximal pain intensity using VAS during the treatment and follow-up period. Among the VAS scores recorded in menstrual diary from 2 days before the onset of menses to the 4th day of menses, the highest VAS score was selected as the maximal VAS of the menstrual cycle. The average of the two maximal VAS scores during the two baseline menstrual cycles was used as the baseline VAS. Secondary outcome parameters included the number of patients who took analgesics and safety evaluation. Safety evaluation was based on physical examination and occurrence of adverse events. Statistical analyses The intention-to-treat (ITT) population, defined as all randomized patients who wore the sericite or placebo belt at least once, was used in all efficacy and safety analyses. Missing values were imputed using last-observation-carriedforward (LOCF) method for subjects who did not complete the study. The results of descriptive analyses at baseline are reported as the mean and standard deviation. The differences in baseline characteristics between groups were 190 C.H. Lee et al. Assessed for eligibility (n=141) Pre-treatment baseline period (2 menstrual cycles) Excluded E l d d ((n=37) 37) -not meeting the inclusion criteria(n=7) -menstrual diary not complete (n=30) Randomized (n=104) Sericite belt (n=52) Placebo belt (n=52) Wear belt for 3 menstrual cycles Wear belt for 3 menstrual cycles Lost to follow-op (n=6) - Withdrawal of consent (n=6) Lost to follow-op (n=9) - Withdrawal of consent (n=8) - No explanation (n=1) Post-treatment follow-up period (2 menstrual cycles) Post-treatment follow-up period (2 menstrual cycles) Analyzed (n=52) Analyzed (n=52) Figure 2 Flow of patients through the trial. examined using Student’s t-test or Wilcoxon’s rank-sum test for continuous variables and Chi-square test for categorical variables. The values of maximal VAS at each menstrual cycle were compared between groups using analysis of covariance (ANCOVA). The ANCOVA model included fixed effect for center and baseline VAS value as a covariate. In addition to p-values, least square means for the two treatments and differences between groups at each menstrual cycle were estimated from the ANCOVA together with 95% confidence intervals. For the primary endpoint, adjustments for multiple comparisons with the use of a Bonferroni-Holm procedure were incorporated into the analyses. The use of Table 1 analgesics and occurrence of adverse events between groups were analyzed by Chi-square test and Fisher’s exact test, respectively. All reported p values were from 2-sided tests and considered significant at p < 0.05. All statistical analyses were performed using SAS software version 9.2 (SAS Institute Inc., Cary, NC, USA). The sample size was estimated using the Power Analysis and Sample Size for Windows software (Package PASS 2008, NCSS, Kaysville, UT, USA). A sample size of 43 patients per group was required to detect a mean VAS score difference of 2.0 between the experimental and the control group, with at least 80% power and an ˛ level of 0.05 (2-sided t-test), Demographic and menstrual characteristics of study population. Age Height Weight Menarche (years) Family history of dysmenorrhea Yes No Parity Nulliparous Multiparous Cycle length (days) Maximal pain intensity (VAS) Analgesic use during menstruation Yes No Sericite group (n = 52) Control group (n = 52) p value 27.6 ± 6.2 162.1 ± 5.0 55.2 ± 7.3 13.6 ± 1.4 28.1 ± 6.3 162.2 ± 5.0 55.5 ± 7.4 13.3 ± 1.3 0.855 0.794 0.883 0.140 0.556 29 23 26 26 42 10 30.4 ± 4.0 7.3 ± 1.4 40 12 30.0 ± 4.2 7.4 ± 1.4 36 16 42 10 0.631 0.098 0.663 0.497 Efficacy and safety of sericite belt in women with primary dysmenorrhea 191 dysmenorrhea gradually returned to the baseline VAS score in the control group. As a result, there was significant difference in the maximal VAS score at cycle 5 (5.08 ± 0.31 vs. 6.47 ± 0.31, difference −1.39 [95% CI, −2.25 to −0.53], p = 0.0017) between the groups. Thirty-six and 42 patients took pain medications at baseline period in the sericite and control groups, respectively (Table 3). Although the number of patients who used analgesics decreased over the treatment period (29 in the sericite group and 19 in the control group at cycle 3), no significant differences were found between the groups. During the follow-up period, the number of patients who took analgesics further decreased from 29 to 26 in the sericite group, whereas it increased from 19 to 25 in the control group. However, there were no significant differences between the groups. Figure 3 Change in maximal VAS score between sericite and control groups during the study period. assuming a standard deviation of 2.73. We tried to recruit 51 patients per group into the study to compensate for an expected dropout rate of 15%. Results Patient disposition and baseline characteristics One hundred forty-one patients with dysmenorrhea were recruited and screened for the study (Fig. 2). Thirty-seven patients were excluded before randomization because they were diagnosed with secondary dysmenorrhea (n = 7) or did not fill out their menstrual diary completely during the pre-treatment baseline period (n = 30). One hundred four patients were randomized to wear a sericite (sericite group) or placebo belt (control group), with all 52 women in each group included in the analysis. Six patients in the sericite group and nine patients in the control group were lost to follow-up during the treatment period. Among 89 patients who completed the study, 83 patients (41 in the sericite group and 42 in the control group) wore the sericite or placebo belt at least 70% of the total days of the 3 menstrual cycles. The baseline characteristics are presented in Table 1. There were no significant differences in age, age at menarche, length of menstrual cycle, parity, maximal VAS score, and analgesic use between the groups. Efficacy The change in maximal VAS score during the study period is shown in Table 2 and Fig. 3. The VAS scores were highest during the baseline cycle and were comparable between groups (7.27 ± 0.19 vs. 7.38 ± 0.19, p = 0.664). The intensity of menstrual pain decreased over time for both groups during the treatment period, with major improvements observed at the third menstrual cycle (4.96 ± 0.30 vs. 5.69 ± 0.30, p = 0.087). Although both groups showed significant improvements compared with the baseline VAS score, there were no differences between the groups. During the follow-up period, the earlier improvement in dysmenorrhea was maintained in the sericite group, whereas the improvement in Safety Reporting of adverse events did not differ between the groups (Table 4). Seventeen adverse events were reported by 15 patients (14.4%). The most common adverse events were first degree burns (41.2%) owing to the hot pack and itching (35.3%), with an equal frequency in both groups. All of these adverse events disappeared within a few days without treatment. There were no serious adverse events and no clinically relevant changes in vital signs. No patient discontinued the clinical trial due to an adverse event. Discussion Our results indicate that, although not statistically significant between groups, the VAS scores decreased in both groups compared with baseline during the treatment period. However, during the follow-up period, statistically significant difference in the VAS scores between groups was observed. This difference arose mainly because the reduced VAS score was stable and maintained in the sericite group, whereas it gradually increased in the control group. A similar decrease in the VAS score during the treatment period in both groups could be partly attributable to the effect of the hot pack. Hot packs are known to have beneficial effects in dilating blood vessels, increasing blood flow, and influencing transmission of pain by reducing the level of nociceptive stimulation.17,18 It has been demonstrated that continuous low-level topical heat therapy with a patch or a wearable heat wrap applied directly on the skin of the lower abdomen provides significant pain relief in patients with dysmenorrhea.19,20 However, the sustained pain relief in the sericite group during the follow-up period suggests that, although the effect was masked by the hot pack during the treatment period, the sericite belt reduced the severity of dysmenorrhea. In addition, there were no statistically significant differences in adverse events, and the events were generally minor and short in duration. This is the first clinical trial to provide evidence that a sericite belt might be an effective and safe non-pharmacologic alternative for the treatment of primary dysmenorrhea. Although the precise mechanism underlying sericite’s efficacy for dysmenorrhea is still unclear, one possible mechanism is the thermal effect of FIR rays from sericite, 192 Table 2 C.H. Lee et al. Comparison of maximal VAS score at each menstrual cycle. Sericite group (n = 52) LS mean ± SE Baseline Cycle 1 Cycle 2 Cycle 3 Cycle 4 Cycle 5 7.27 5.89 6.13 4.96 5.04 5.08 ± ± ± ± ± ± Control group (n = 52) LS mean ± SE 0.19 0.30 0.33 0.30 0.34 0.31 7.38 6.33 5.72 5.69 5.97 6.47 ± ± ± ± ± ± 0.19 0.30 0.33 0.30 0.34 0.31 Group difference LS mean (95% CI) p valuea −0.12 −0.43 0.41 −0.73 −0.93 −1.39 0.664 0.309 0.380 0.087 0.0584 0.0017* (−0.65, (−1.27, (−0.51, (−1.57, (−1.88, (−2.25, 0.42) 0.41) 1.33) 0.11) 0.03) −0.53) Abbreviations: CI, confidence interval; LS Mean, least square mean; SE, standard error. a p value was based on analysis of covariance (ANCOVA) with center as fixed effect and baseline value as a covariate. * Significant difference after Bonferrroni—Holm adjustment for multiple comparisons (p = 0.010). Table 3 Number of patients who took pain medications during the study period. Sericite group (n = 52) N (%) Baseline Cycle 1 Cycle 2 Cycle 3 Cycle 4 Cycle 5 36 (69.2) 29 (55.8) 31 (59.6) 29 (55.8) 25 (48.1) 26 (50.0) which is announced as the most outstanding natural mineral emitting FIR rays.21 FIR can penetrate through skin and transfer energy into deep tissue gradually through a resonance-absorption mechanism of organic and water molecules without irritating or overheating the skin.22,23 The skin temperature steadily increased to a plateau at approximately 38—39 ◦ C during the treatment of FIR for 30—60 min as long as the distance between the ceramic plate and the skin was more than 20 cm.24 The technology of thermal therapy using FIR has been widely applied in medicine and shown to be beneficial in the treatment of chronic pain14 and chronic fatigue syndrome,13 and wound healing.12 In addition, some studies have demonstrated that thermal therapy with FIR improves hemodynamics in congestive heart failure by thermal vasodilation,25,26 and improves blood flow in patients with peripheral arterial occlusive disease.27 These findings suggest that FIR could be applied to the management of primary dysmenorrhea because the uterine muscle ischemia and hypoxia are thought to be the origin of pain Table 4 Control group (n = 52) N (%) 42 (80.8) 28 (53.8) 25 (48.1) 19 (36.5) 25 (48.1) 25 (48.1) p value 0.497 0.895 0.423 0.149 1.000 0.889 in primary dysmenorrhea. Recently, it was shown in Korea that underwear emitting FIR rays was effective in reducing the severity of dysmenorrhea. One hundred twenty-one women with dysmenorrhea were enrolled and the intensity of dysmenorrhea using VAS before and after wearing underwear emitting FIR for one menstrual cycle was compared. Decrease of VAS was observed (mean and standard deviation: 3.45 ± 2.09, p < 0.001) and the compliance of wearing underwear was correlated with the decrease of dysmenorrhea. Matsushita et al.28 reported the effect of FIR-ray dry sauna in 13 patients with fibromyalgia. Pain reduction of 20—78% was achieved after treatment and the effect was maintained throughout the mean observation period of 14 months, which is consistent with our finding of a prolonged effect of a FIR-emitting sericite belt for dysmenorrhea. Our study has at least two limitations. First, because the outcomes were patient-reported and subjective, it is possible that the sericite belt has only a placebo effect. However, whereas the placebo effect lose efficacy with time, the Frequency of reported adverse events. 1st degree burn Skin rash Itching Abdominal discomfort Nausea Total Sericite group (52) N (%) Control group (52) N (%) p value 3 (5.8) 1 (1.9) 4 (7.7) 1 (1.9) 1 (1.9) 10 4 (7.7) 0 (0) 2 (3.8) 0 (0) 1 (1.9) 7 1.00 1.00 0.68 1.00 1.00 Efficacy and safety of sericite belt in women with primary dysmenorrhea severity of pain gradually decreased during the treatment period and was maintained during the follow-up period in our patients.29 Second, because the patients were allowed to take analgesics that they usually used, this might have influenced the results. During this study, dozens of analgesic drugs with different brand names and different ingredients were taken by participants. Because the analgesic drugs differed among patients and, furthermore, many participants took two or three kinds of analgesic drugs in one menstrual cycle, we could not directly compare the amount of analgesics used between groups and determine if there were differences in the use of analgesics between groups. This might be the reason why the significant decrease in VAS score was not reflected in the reduction in the number of patients who took analgesics in this study. In conclusion, these results suggest that a FIR-emitting sericite belt with a hot pack is an effective and safe treatment option with a prolonged effect for the management of primary dysmenorrhea and could be beneficial for patients unwilling or unable to tolerate current therapies, such as NSAIDs and OCs. Conflicts of interest The authors have no personal or financial conflicts of interest associated with this work. References 1. Proctor ML, Smith CA, Farquhar CM, Stones RW. 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