ACUTE PAIN SECTION. Patients. The patients were 52 women with primary dysmenorrhea.

Transcription

1 Pain Medicine 2010; 11: Wiley Periodicals, Inc. ACUTE PAIN SECTION Original Research Article A Comparative Study on the Immediate Effects of Electroacupuncture at Sanyinjiao (SP6), Xuanzhong (GB39) and a Non-Meridian Point, on Menstrual Pain and Uterine Arterial Blood Flow, in Primary Dysmenorrhea Patientspme_ Yu-Xia Ma, MD, PhD,* a Liang-Xiao Ma, MD, PhD, a Xue-lian Liu, MD,* Yu-Xiang Ma, Kun Lv, MD, * Dong Wang, MD,* Jian-ping Liu, MD, PhD, Jian-min Xing, PhD, Hui-juan Cao, MD, Shu-Zhong Gao, MD,* and Jiang Zhu, MD *Shandong University of Traditional Chinese Medicine, Jinan, China; Beijing University of Chinese Medicine, Beijing, China; Shandong Institute of Medical Imaging, Jinan, China Reprint requests to: Shu-Zhong Gao, MD, Shandong University of Traditional Chinese Medicine, University Science Park, Chang-Qing District, Jinan , China. Tel: ; Fax: ; gaoshuzhong@163.com. Jiang Zhu, MD, School of Acupuncture and Moxibustion, Beijing University of Chinese Medicine, NO 11 Bei San Huan Dong Lu, Chaoyang District, Beijing China. Tel: ; Fax: ; jzhjzh@263.net. a These two authors and their affiliations contributed equally to this work. Co-Corresponding: Shu-Zhong Gao, Jiang Zhu. Abstract Objective. The objective of this study was to compare the effects of Sanyinjiao (SP6), Xuanzhong (GB39), and an adjacent non-meridian point on menstrual pain and uterine arterial blood flow in primary dysmenorrhea patients. Design. The design of the study was a prospective, randomized controlled trial. Setting. The setting of the study was the Shandong Institute of Medical Imaging, Jinan, China. Patients. The patients were 52 women with primary dysmenorrhea. Interventions. Women received electroacupuncture (EA) at SP6 (n = 13), GB39 (n = 14), and an adjacent non-meridian point (n = 12), respectively, for 10 minutes when scored 40 on a 100-mm visual analog scale (VAS), and for 30 minutes on the next 2 days. There was no EA in the waiting list group (n = 13). Outcome Measures. Primary outcomes were menstrual pain, resistance index (RI), and the ratio between peak systolic to end-diastolic flow velocity (S/D) in uterine arteries. Secondary outcomes included verbal rating scale (VRS) and retrospective symptom scale (RSS). Results. The SP6 group had a highly significant reduction in VAS scores compared with the waiting list group ( mm, 95% confidence interval [CI] to , P < ), GB39 group ( mm, 95% CI to -9.88, P < ) and the non-meridian point group ( mm, 95% CI to , P < ), respectively. A significant reduction in VRS scores was found in the SP6 group compared with the GB39 group (P = 0.034) and the non-meridian point group (P = 0.038). There were no significant differences of RI, S/D-values and RSS scores among the four groups (P > 0.05). Conclusions. EA at SP6 can immediately relieve menstrual pain and minimize the influence of pain on daily life compared with GB39 and an adjacent non-meridian point. The data preliminarily show the specificity of SP6 for the immediate pain relief of primary dysmenorrhea. Keywords. Electroacupuncture; Primary dysmenorrhea; Sanyinjiao (SP6); Uterine arterial blood flow; Acupoint specificity 1564

2 Acupuncture Analgesia Effect in Primary Dysmenorrhea Introduction Dysmenorrhea is the occurrence of painful menstrual cramps of the uterus. It can be divided into two broad categories: primary and secondary dysmenorrhea. Primary dysmenorrhea is defined as painful menstruation with no detectable organic disease. It is the most common gynecologic complaint, especially among young females [1,2]. Despite differences in measurement methods, the prevalence of primary dysmenorrhea has been found to be high in samples of various countries, varying from 45.3% to 89.5% [3 8]. Primary dysmenorrhea has been reported as the leading cause of recurrent short-term school absence in adolescent girls [9,10], and is a common problem in women of reproductive age [11]. Data show that excessive production and release of endometrial prostaglandins (PGs) during menstruation may be a significant factor in inducing uterine hypercontractility, reducing uterine blood flow, uterine hypoxia and hypersensitizing pain fibers [12 17]. Women with primary dysmenorrhea have elevated Doppler indices throughout the whole cycle, suggesting high impedance against blood flow within the uterus [18]. Uterine artery blood flow has been found to be reduced in dysmenorrhea [19]. Based on this understanding, modern pharmacological therapies for primary dysmenorrhea commonly focus on alleviating menstrual pain and relaxing uterine muscle contraction by using non-steroidal anti-inflammatory drugs (NSAIDs) [20 23] or oral contraceptive pills [23]. However, treatment with NSAIDs is associated with a number of side effects and in 20 25% of cases, menstrual pain has been shown to be inadequately controlled by NSAIDs alone [24]. Therefore, finding an effective nonpharmacological method for relieving primary dysmenorrhea has a significant potential value. Acupuncture is recommended as a safe treatment [25] and has long been indicated for primary dysmenorrhea in China. Although, previously published studies have reported effective treatment of dysmenorrhea with acupuncture [26 28], and with high frequency transcutaneous electrical nerve stimulation (TENS) [29], because of low methodological quality and small sample size, there is no convincing evidence for acupuncture in the treatment of primary dysmenorrhea [29,30]. Thus, there is a need for high-quality randomized, blinded, placebo-controlled trials to assess the effects of acupuncture on primary dysmenorrhea. In the clinical practice of acupuncture, various acupoints are used for dysmenorrhea. Sanyinjiao (SP6) is found to be one of the most commonly used points encountered when searching ancient Chinese medical classics, Chinese acupuncture textbooks [31], and recent clinical studies [32 34]. According to the theory of ancient Chinese acupuncture, female fertility and reproductive homeostasis mainly depends on the abundance and harmonization of qi and blood, which are closely related to the organs spleen, liver, and kidney. SP6 is the junction point of the spleen, liver, and kidney meridians. It is considered to fortify the spleen, nourish the liver and the kidney, and regulate and harmonize qi and blood. Therefore, SP6 is commonly used for gynecological indications. The objective of our study was to provide conclusive evidence that SP6 is specific for primary dysmenorrhea. Considering that menstrual pain is usually assessed by visual analog scale (VAS) [35,36] and is closely related to uterine arterial blood flow [17 19,37,38], we used VAS, other clinical scale assessments, and the color Doppler sonography (CDS) to investigate the specificity of SP6 in relation to dysmenorrhea, when compared with the same spinal segments-controlled acupoint (Xuanzhong, GB39) and an adjacent non-meridian point as separate controls in this study. Methods A prospective, randomized controlled clinical trial was carried out to compare the effects of electroacupuncture (EA) at SP6, GB39, and an adjacent non-meridian point on menstrual symptoms and uterine arterial blood flow in primary dysmenorrhea. Clinical scale assessments, including VAS, verbal rating scale (VRS) [39], and retrospective symptom scale (RSS) [40], as well as CDS were used. A group without any acupuncture intervention (waiting list group) was also designed as an additional control group. The Medical Ethics Committee of Beijing University of Chinese Medicine approved the trial. As the trial was conducted in Jinan, China, a local ethics committee called the National Drug and Clinical Investigation Ethics Committee in the Affiliated Hospital of Shandong University of Traditional Chinese Medicine also approved this trial. In this study, women with primary dysmenorrhea from four universities in Jinan, Shandong province of China and Affiliated Hospital of Shandong University of Traditional Chinese Medicine were recruited. The trial was conducted in Shandong Institute of Medical Imaging, Jinan, China. Eligible participants met the following inclusion criteria: 1) met the diagnostic criteria of primary dysmenorrhea in the Primary Dysmenorrhea Consensus Guideline [41]; 2) aged from 15 to 30 years old without history of delivery; 3) with normal menstrual cycle (28 7 days); 4) course of dysmenorrhea varying from 6 months to 15 years; 5) experienced menstrual pain scoring more than 40-mm on a 100-mm VAS during the baseline menstrual period (one period prior to present menstrual period with treatment) according to the patient-kept dairy; and 6) no oral administration of any analgesic nor acceptance of other therapies 24 hours before the trial. Women with secondary dysmenorrhea caused by endometriosis, uterine myomas, endometrial polyps, pelvic inflammatory disease, and other gynecological problems, were excluded. Women allergic to aspirin were excluded. Considering that some Chinese people may have a basic knowledge of acupoints and acupuncture, participants with history of acupuncture treatment and knowledge of the effects of acupoints were excluded. 1565

3 Ma et al. Participants were enrolled between November 30, 2007 and July 15, At the day of inclusion visit, informed consent was obtained from each participant. If those in the waiting list group required any acupuncture treatment after two observation menstrual periods, they were allowed to be treated for three sessions during the third menstrual period. All eligible participants were provided with a dairy for recording information on menstrual symptoms at baseline, treatment, and follow-up periods. Randomization Procedure Participants random numbers, by means of a computergenerated, blocked random-allocation sequence with a block size of 4 (random list generated with SPSS 17.0 [SPSS Inc., Chicago, IL]), were administered by a blinded statistician, from an independent institution not involved in the study (Evidence-Based Medicine Center of Beijing University of Chinese Medicine), to assign participants to the intervention groups. The randomization procedure took place just 5 minutes before the first treatment session. Interventions Participants were randomized before intervention to either an SP6 treatment group, a GB39 control group, a nonmeridian point control group, or a waiting list control group. The points used in this study (SP6 and GB39) were located according to Chinese National Criteria for Points Location (GB ) issued in SP6 is located at 3 cun (unit of length for measurement in locating points by dividing a certain part of the patient s body into certain divisions of equal length) above the medial malleolus, at the posterior border of the medial aspect of tibia. GB39 is located at 3 cun above the tip of the external malleolus, at the anterior of fibula. An adjacent non-meridian point located at the midpoint between the Stomach and Gallbladder Meridians in the same level of SP6 and GB39 was selected. Direction and depth of needling were determined in accordance with the Meridians and Acupoints, which is the textbook for national Traditional Chinese Medicine (TCM) universities in China. Participants in the three groups with acupuncture interventions received three treatment sessions, with 10 minutes in the first session, then 30 minutes on the next 2 days, and once a day for 3 days. To ensure equal participant blinding in the groups and consistency of treatment, acupuncture interventions for the three groups were performed by the same acupuncturist throughout entire study. There was no variation in acupuncture techniques and stimulating intensities of EA among the three treatment groups. The acupuncturist had completed a 5-year full-time training of acupuncture and traditional Chinese medicine, and 2 years clinical experience in an academic acupuncture clinic. The acupuncturist recorded any adverse events. In the three acupuncture treatment groups, participants were placed in a supine position, then mm stainless sterilized disposable needles (Hanyi, Beijing Hanyi Medical Instruments Center, Beijing, China) were inserted to either SP6, GB39, or non-meridian point perpendicularly and bilaterally to a depth of mm. Basic needling techniques of lifting thrusting and twirling were used for about 1 minute in all three treatment groups to induce needling sensation (De Qi), although no attempt was made to evoke De Qi in the non-meridian point group. After De Qi, another non-meridian point located at 2 mm above each of these three treatment points, respectively, was punctured very superficially to a depth of 2 mm without De Qi. This point was used as another stimulation lead of EA. There was no limitation of positive and negative lead connection. Two electric clips of one output line of point electric stimulating device (HANS-200, Jisheng Medical Science and Technology Company Lit., Nanjing, China) were put on two points on the same side of the body (i.e., connecting right SP6 and the right nonmeridian point 2-mm vertically above SP6 with one electric line). EA with 2/100 Hz (an alternately dense and sparse wave, which alternates between 2 Hz and 100 Hz waves at 1.5-second intervals) at the highest intensity each woman could tolerate was applied for 10 minutes for participants in all three treatment groups. No EA treatment was administered in the waiting list control group. All participants were instructed to use aspirin alone for pain relief as needed (VAS > 80 mm) and were not given or permitted any other form of treatment during the study. The assigned analgesic medication usage had to be documented in the dysmenorrhea diary during two menstrual periods after randomization. Blinding Participants were blinded to treatment, as those who had history of acupuncture treatment and knew the effects of acupoints were excluded. The acupuncturist maintained neutral communications with all participants and avoided providing cues that might reveal whether she was performing acupuncture with real or sham acupoints. In the process of trial, only the acupuncturist knew the treatment allocation and was separated from the imaging technician. Moreover, the punctured area was covered during the needle retention time, thus, blinding the imaging technician to treatment allocation. The assessor who recorded the results of clinical scale assessments after treatment was also blinded to treatment allocation. Outcome Measures Baseline data including age, course of disease, scores of VAS, VRS, and RSS, were carefully recorded. VAS scores were recorded again at midpoint (retaining needles for 5 minutes) and end of first treatment (retaining needles for 10 minutes), as well as 30 minutes after the end of first treatment to evaluate the credibility of interventions on relieving menstrual pain. Meanwhile, RI and S/D were assessed at midpoint (retaining needles for 5 minutes) and 1566

4 Acupuncture Analgesia Effect in Primary Dysmenorrhea end of the first treatment (retaining needles for 10 minutes) by the same imaging technician to evaluate the effects of interventions on uterine artery blood flow. VRS and RSS scores were recorded again at the end of menstrual period during which the treatment was done and next follow-up period by phone interview. Primary Outcome Measures VAS [36] Intensity of menstrual pain was assessed four times before and after intervention (before intervention, 5 minutes after EA or resting, 10 minutes after EA or resting, 30 minutes after end of intervention), respectively, on a 100-point VAS (0 represented no pain and 100 represented maximum imaginable pain). Women marked their present pain on a pain drawing. RI, S/D ratio Type-B ultrasonic diagnostic apparatus ALOKA (Aloka Co., Tokyo, Japan) SSD-5500 with convex probe ( MHz) was used to assess resistance index (RI) values and the ratio between peak systolic to end-diastolic flow velocity (S/D) in uterine ascending arteries. Participants were asked to have a moderately filled urinary bladder for the first measurement. Then CDS was conducted after participants had rested for 5 minutes by lying on the exam bed. Values of RI and S/D were measured again at 5 minutes and 10 minutes after EA or resting, respectively. The same medical imaging technician made all measurements. Secondary Outcome Measures VRS [39] The influence of menstrual pain on daily work, associated general symptoms, and the condition of oral administration of analgesic were assessed at end of baseline menstrual period, present treatment period and next follow-up period, respectively, by VRS (Table 1). RSS [40] Participants were interviewed by phone to rate menstrual symptoms for frequency and severity of occurrence, on the basis of their experiences of their last menstrual period. Total frequency (RSS-COX1) refers to the total amount of time of participant experienced a condition during their last period, while average severity (RSS- COX2) refers to the average level of pain or distress of the condition when it occurred (Table 2). Phone interviews were conducted three times, respectively, at end of baseline menstrual period, present treatment period, and next follow-up period. The process of our trial was as follow: 1) Eligible participants were assessed on their menstrual symptoms by VRS and RSS at the end of last menstrual period (baseline period). 2) VAS values were measured at the first day of Table 1 Items Influence of pain on daily work Associated general symptoms Administration of analgesic Total scores: present menstrual period when VAS 40 mm, while RI value and S/D ratio in uterine arteries in each participant were measured 5 minutes before interventions and the respective minimal values were recorded. 3) SP6, GB39, or non-meridian point was needled immediately and basic lifting thrusting and twirling method was performed for about 1 minute for De Qi. The needles were retained for 10 minutes with EA, and participants assigned to the waiting list group rested on the bed for 10 minutes without EA. During the time of needle retention or resting, CDS was conducted to monitor uterine blood flow and values of RI and S/D were recorded at 5 minutes and 10 minutes respectively, after EA or resting. Meanwhile, VAS values were measured at 5 minutes and 10 minutes, respectively, after EA or resting. 4) The needles were then removed to end the first treatment. VAS values were measured again 30 minutes after the end of interventions. 5) Another two acupuncture sessions were conducted in the next 2 days for three needling groups. 6) Participants were interviewed by phone again to assess their menstrual symptoms by VRS and RSS at end of present menstrual period and next follow-up period to end the trial. Figure 1 illustrates the procedure of recruitment, intervention and measurement. Statistic Analysis Verbal rating scale Ratings Not noticeable (0) Slightly bothersome (1) Moderate bothersome (2) Severely bothersome (3) No (0) Yes (1) Never (0) Occasionally (1 time) (1) Regularly (more than 1 time) (2) No effect (3) Note: 1. Please mark in the corresponding items and alculate the total scores and record it. 2. General symptoms include pale complexion, flushing, nausea, vomiting, headaches, weakness, diarrhea, etc. Means and standard deviations (SD) were determined for all data including the scores of VAS, VRS, RSS, and values of RI and S/D. As all data were measured at several different times, these belonged to repeated measures data. Thus, analysis of variance with repeated measures was used to analyze all data [42,43]. Between-groups comparisons were conducted to show the differences of values at several times among the four groups. The results were analyzed with Statistical Package for the Social Sciences (SPSS) for Windows (version 17.0, SPSS Inc., Chicago, IL). In this study, we considered P < 0.05 to be significant. 1567

5 Ma et al. Table 2 Retrospective Symptom Scale on Dysmenorrhea Frequency rating (COX 1) Severity rating (OX 2) Condition Scores Dysmenorrhea Nausea Vomiting Loss of appetite Headaches Upper backaches Lower backaches Leg aches Dizziness Weakness Diarrhea one time/day two times/day three times/day four times/day or more Sleeplessness 6 hours >5 hours 5 hours >4 hours 4 hours >3 hours 3 hours Depression Additional time in bed due to menstrual problems Total scores of COX1 Total scores of COX2 Notes: Total frequency rating (COX1): 0 did not occur; 1 lasted less than 3 hours; 2 lasted 3 7 hours; 3 lasted an entire day; 4 lasted several days. Average severity ratings (COX2): 0 not noticeable; 1 slightly bothersome; 2 moderate bothersome; 3 severely bothersome; 4 very severely bothersome. Scores 1568

6 Acupuncture Analgesia Effect in Primary Dysmenorrhea 70 patients were screened 52 recruited and assessed by VRS and RSS for last menstrual (baseline) period 18 did not meet inclusion criteria Endometriosis (n=8) Uterine myomas (n=4) Pelvic inflammation (n=2) Acupuncture knowledge (n=4) Measurements of VAS, RI, S/D at the 1st day of present menstrual period when VAS 40mm Results Patients 13 assigned to the waiting list control group No needling, 10min resting Measurements of VAS, RI and S/D respectively at 5min and 10min after EA, all 52 completed measurement and treatment; Withdrawn the needles; measurement of VAS again 30min after needle withdrawal No needling, 30min resting per day in next 2 days 12 completed the test and included in analysis 1 dropped out due to failure of communication Randomization (n=52) 14 assigned to the GB39 control group Of 70 women referred for the first assessment, 18 did not meet the inclusion criteria (Figure 1). A total of 52 patients were recruited into the trial. Thirteen (13) were assigned to the waiting list control group, 14 to the GB39 control group, 13 to the SP6 treatment group, and 12 to the non-meridian point control group. The baseline characteristics including age, course of disease, age of menarche, VRS and RSS scores of last menstrual period, as well as values of VAS, RI, S/D of present period just before interventions, were similar in the four groups (Tables 3 and 4). Thus, the randomization process was effective in producing groups with equivalent variable outcomes at baseline. 13 assigned to the SP6 treatment group EA at different points for 10min Interview by phone at end of this treatment menstrual period and next follow-up menstrual period to complete the assessment of VRS and RSS 14 completed the test and included in analysis EA at different points for 30min per day in next 2 days 12 completed the test and included in analysis 1 dropped out due to unable to continue next 2 treatments 12 assigned to the non-meridian point control group 12 completed the test and included in analysis Figure 1 Flowchart of participants through the study. VRS = verbal rating scale; RSS = retrospective symptom scale; RI = resistance index; S/D = peak systolic to end-diastolic flow velocity; VAS = visual analog cycle; SP6 = Sanyinjiao; GB39 = Xuanzhong. After the end of first treatment, one woman, who could not be contacted for follow-up, was dropped from the waiting list group. One woman in the SP6 group dropped out because she did not continue the next two treatments (Figure 1). S/D-values of six cases (2 from the waiting list group, 2 from the GB39 group, 1 from the SP6 group, and 1 from the non-meridian point group) could not be recorded for final analysis due to invisible values of enddiastolic flow velocity. Comparisons of VAS Scores at Four Times of Patients in Four Groups As a subjective criterion, decreasing VAS scores indicates a reduction in menstrual pain. Test of within-subjects effects of repeated measures analysis of variance revealed 1569

7 Ma et al. Table 3 Baseline characteristics of 52 patients in four groups Group A (waiting list control group) (n = 13) Group B (GB39 control group) (n = 14) Group C (SP6 treatment group) (n = 13) Group D (non-meridian point control group) (n = 12) P value Age, years * Course of disease, ** months Age of menarche, years * VRS (last menstrual * period), marks RSS-COX1 (last * menstrual period), marks RSS-COX2 (last * menstrual period), marks VAS (present menstrual period), marks ** * P values from between-groups comparisons using Kruskal-Wallis Test. ** P values from between-groups comparisons using one-way analysis of variance. VRS = verbal rating scale; RSS-COX1 = frequency rating of the retrospective symptom scale; RSS-COX2 = severity rating of the retrospective symptom scale; VAS = visual analog scale. Mean standard deviation is given for each parameter. that VAS scores at baseline, 5 and 10 minutes after EA or resting, and 30 minutes after end of intervention in all four groups were gradually decreased in a time-dependent manner (P < ) and a treatment time interaction (P < ). Between-groups pairwise comparisons showed that the SP6 treatment group had a highly significant reduction in VAS scores at four measurement times compared with the waiting list group ( mm, 95% confidence interval [CI] to , P < ), the GB39 group ( mm, 95% CI to -9.88, P < ) and the non-meridian point group ( mm, 95% CI to , P < ), respectively (Figure 2). There were no significant differences in VAS scores at four times between the waiting list group, the GB39 group (P = 0.292), and the non-meridian point group (P = 0.594), respectively, as well as between the GB39 group and the non-meridian point group (P = 0.662). Table 4 Comparisons of RI and S/D-values of Uterine Arterial Flow at Three Times of Patients in Four Groups Between-groups pairwise comparisons showed that there were no significant differences of RI (Figure 3) and S/Dvalues (Figure 4) between every two of the four groups (P > 0.05). Comparisons of VRS, RSS-COX1, and RSS-COX2 Scores at Three Menstrual Periods of Patients in Four Groups Testing of within-subjects effects of repeated measures analysis of variance on VRS scores at baseline period, present treatment period and next follow-up period revealed the effect of time (P < ); however, treatment time interaction (P = 0.205) had no effect. Baseline values of RI and S/D of uterine arterial flow of patients in four groups Group A (waiting list control group) Group B (GB39 control group) Group C (SP6 treatment group) Group D (non-meridian point control group) P value RI (n = 13) (n = 14) (n = 13) (n = 12) S/D (n = 11) (n = 12) (n = 12) (n = 11) Mean standard deviation is given for each parameter. P values from between-groups comparisons using Kruskal-Wallis Test. No records of S/D-values in six cases due to invisible values of end-diastolic flow velocity. RI =resistance index; S/D = peak systolic to end-diastolic flow velocity; SP6 = Sanyinjiao; GB39 = Xuanzhong. 1570

8 Acupuncture Analgesia Effect in Primary Dysmenorrhea Pain intensity on VAS scores, mm Time (minutes) waiting list GB39 Between-groups pairwise comparisons of VRS scores (Figure 5) showed that the SP6 group had significant reduction in VRS scores at three periods compared with the GB39 group (-0.55, 95% CI to , P = 0.034) and the non-meridian point group (-0.57, 95% CI to -0.31, P = 0.038), respectively. There were no significant reductions in VRS scores at three periods between the waiting list group, the GB39 group (P = 0.850), the SP6 group (P = 0.061), and the nonmeridian point group (P = 0.832), respectively, as well as between the GB39 group and the non-meridian point group (P = 0.975). Between-groups pairwise comparisons of both RSS- COX1 (Figure 6) and RSS-COX2 scores (Figure 7) showed SP6 Non-meridian point Figure 2 Development of the mean VAS scores at baseline, 5 and 10 minutes after interventions, and 30 minutes after end of interventions in four groups. VAS, visual analog scale; SP6 = Sanyinjiao; GB39 = Xuanzhong. RI values Time (minutes) waiting list GB39 SP6 Non-meridian point Figure 3 Development of RI values of uterine arterial flow at baseline, 5 and 10 minutes after interventions in four groups. RI, resistance index; SP6 = Sanyinjiao; GB39 = Xuanzhong. S/D values that there were no significant differences between every two of the total four groups (P > 0.05). Side Effects No adverse events were reported in any of the four groups during the trial. Discussion Time (minutes) waiting list GB39 The main finding of this study was that EA at SP6 had significant immediate effect on menstrual pain compared with GB39, an adjacent non-meridian point, and SP6 Non-meridian point Figure 4 Development of S/D-values of uterine arterial flow at baseline, 5 and 10 minutes after interventions in four groups. S/D, peak systolic to end-diastolic flow velocity; SP6 = Sanyinjiao; GB39 = Xuanzhong. VRS scores waiting list GB39 SP6 Non-meridian point Baseline Present period Next period Figure 5 Development of the mean VRS scores at baseline (last menstrual period), after interventions (present period) and follow-up (next period) in four groups. VRS, verbal rating scale; SP6 = Sanyinjiao; GB39 = Xuanzhong. 1571

9 Ma et al. RSS-COX1 scores Baseline Present period Next period waiting list GB39 no-acupuncture. SP6 had no significant effects on RI and S/D-values of uterine artery flow compared with three controls. SP6 minimized the influence of menstrual pain on daily work, relieved associated general symptoms, and decreased the dosage of oral analgesic assessed by VRS compared with GB39 and non-meridian point. However, SP6 had no significant effect on frequency and severity of occurrence of menstrual symptoms assessed by RSS compared with above two control points. According to the meridian theory of Chinese acupuncture, SP6 is the junction point of spleen, liver, and kidney meridians, and is closely related to lower abdomen and uterus. SP6 Non-meridian point Figure 6 Development of the mean RSS-COX1 scores at baseline (last menstrual period), after interventions (present period) and follow-up (next period) in four groups. RSS-COX1, frequency rating of the retrospective symptom scale; SP6 = Sanyinjiao; GB39 = Xuanzhong. RSS-COX2 scores Baseline Present period Next period waiting list GB39 SP6 Non-meridian point Figure 7 Development of the mean RSS-COX2 scores at baseline (last menstrual period), after interventions (present period) and follow-up (next period) in four groups. RSS-COX2, severity rating of the retrospective symptom scale; SP6 = Sanyinjiao; GB39 = Xuanzhong. Therefore, needling SP6 is said to promote the flow of qi and blood in the meridians so as to improve the nourishment of thoroughfare vessel, conception vessel, and uterus, and to relieve menstrual pain. Many records of using SP6 for treatment of dysmenorrhea can be found in TCM classical books. Today SP6 remains one of the most commonly used points for gynecologic indications in clinical practice, particularly for alleviating dysmenorrhea [32 34]. Thus, SP6 is claimed as a specific point for dysmenorrhea by traditional Chinese medicine. Our previous trial (which is scheduled for publication in the August 2010 issue of the Journal of Alternative and Complementary Medicine) showed that dysmenorrhea could be relieved by needling SP6 with manual acupuncture. GB39 is a point of gallbladder meridian located at the same level of SP6 on the extremity, and it is rarely used to relieve dysmenorrhea based on Chinese medicine. On the other hand, in terms of anatomy, SP6 is located at the medial aspect of calf where the saphenous nerve is located superficially, and the tibial nerve more deeply. The Saphenous nerve derives from the L4 nerve while the tibial nerve derives from the L5-S1 nerves. Therefore, SP6 is controlled by the L4-S1 nerves. GB39 is controlled by the lateral cutaneous nerve of calf, the deep peroneal nerve and the tibial nerve which derive from the L5 nerve, the L4~S1 nerves and the L5-S1 nerves. So the L4~S1 nerves govern GB39. Therefore, both SP6 and GB39 are controlled by the L4~S1 nerves but they belong to the spleen meridian and the gallbladder meridian, respectively. Review of previous studies of point specificity, reveals the common use of control points which have included treatment-irrelevant acupoints [44], acupoints in the same spinal segments [45,46], nearby acupoints [47], or nonmeridian points [48,49]. Thus, SP6 was used in this study to investigate the specificity of SP6 for primary dysmenorrhea when compared with treatment-irrelevant acupoint GB39 (in the same spinal segments of SP6), and an adjacent non-meridian point (located at the midpoint between Stomach Meridian and Gallbladder Meridian in the same level of SP6 and GB39) used as control points. Previous studies of acupoint specificity, have reported positive [45 48] and negative results [49,50]. The result of this study shows that SP6 was clinically effective in immediately relieving menstrual pain in patients with primary dysmenorrhea assessed by VAS, compared with control points. It suggests that SP6 can significantly reduce symptoms in women with primary dysmenorrhea, while GB39 and adjacent non-meridian point are rarely potent. This finding supports the specificity of SP6 in immediately relieving menstrual pain of patients with primary dysmenorrhea. It was reported that uterine artery blood flow is reduced in dysmenorrhea cases with higher values of PI and RI and S/D ratio [17 19]. However, between-groups comparisons using repeated measurement in our study showed that there were no significant changes of RI and S/Dvalues of uterine artery blood flow between SP6 group and each of other three control groups. This suggests that there was no specificity of SP6 in relation to uterine artery 1572

10 Acupuncture Analgesia Effect in Primary Dysmenorrhea blood flow in patients with primary dysmenorrhea, although it had specificity in immediate menstrual pain relief compared with GB39 and non-meridian point. A factor which could have influenced the result was the small sample size. Additionally, the values of S/D could not be measured in some cases due to invisible values of end-diastolic flow velocity. In future studies, a larger sample trial should be considered to investigate the relationship between the menstrual pain relief and decreased uterine artery blood flow. On the other hand, self-group comparisons using repeated measurement showed that of all four groups in this study, only the SP6 treatment group showed significant reduction in both RI and S/Dvalues before and after interventions. These results suggest that SP6 is effective in improving blood flow in uterine arteries by reducing RI and S/D-values. And that this may be one of the mechanisms whereby SP6 is effective in relieving dysmenorrhea. VRS is a simple, commonly used pain rating scale, originated by Melzack [51], which was used in this study to assess the influence of menstrual pain on patients life. Compared with GB39 and non-meridian point, SP6 could improve performance of daily activities according to VRS. However, there was no significant difference in changes of VRS values between the SP6 group and the waiting list group. This finding does not support the beneficial effects of acupuncture on primary dysmenorrhea in the majority of previously reports [26 29]. Several reasons could be considered. First, the VRS has been found to be less sensitive than the 100 mm VAS [52]. Moreover, the VRS used in this study only varied from 0 to 7 marks (Table 1) which may not correlate with the participants experience. Additionally, the understanding of each rating item may vary between individuals. Regarding changes of RSS-COX1 and RSS-COX2, there were no differences between groups. This finding showed that SP6 had no specificity in relation to RSS. In summary, the strengths of our study include the use of SP6 and primary dysmenorrhea as study point and study disease to prospectively investigate the specificity of a treatment which is based on thousands of years of clinical practice in China. In addition to its prospective design, both a treatment-irrelevant acupoint and nearby nonmeridian point in the same spinal segments were used as control points to assess the specificity of SP6 in relation to primary dysmenorrhea. VAS was used as primary outcome measure to assess the immediate effect at several different times after EA by using repeated measures. Compared with VRS and RSS, which should be assessed several days after interventions or at end of next follow-up period, immediate changes on menstrual pain after interventions assessed by VAS are more credible due to both fewer and lesser complex external variables. Finally, we would like to discuss the limitations of this study. The sample size of this study was small. Although it serves as a pilot study, no power analysis was performed which lowers the statistical power of the study. The inability to blind acupuncturists to verum vs sham acupuncture points may cause the acupuncturist to inadvertently communicate an enthusiastic attitude to the participants when applying verum vs sham acupuncture. Finally, the lack of sham acupuncture (nonpenetrating sham acupuncture) used for participants in the waiting list group, may have resulted in a negative bias due to lack of touch and attention received in the acupuncture group. Although acupuncture is effective in the treatment of many clinical conditions, its specificity remains a crucial area in acupuncture research, where many questions remain unanswered. This study serves as a pilot study focusing on the specificity of SP6 in relation to primary dysmenorrhea, and is not conclusive for point specificity. Further RCTs with larger sample sizes with reasonable power analysis are needed to provide more reliable evidence. Conclusions This study shows that EA at SP6 had superior effects on immediately relieving menstrual pain as assessed by VAS, and minimizing the influence of pain on daily life and work as assessed by VRS compared with GB39 and adjacent non-meridian point. SP6 had no significant effects on frequency and severity of occurrence of menstrual symptoms assessed by RSS and on RI and S/D-values of uterine artery flow compared with the above two control points. 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