Primary dysmenorrhea is defined as menstrual pain in the absence of any organic cause and is most common in women under the age of 25. Primary dysmenorrhea’s characteristic symptom is crampy, colicky spasms of pain in the suprapubic area, occurring within 8–72 hours of menstruation and peaking within the first few days as menstrual flow increases[1]. In addition to painful cramps, many women with primary dysmenorrhea experience other menstrual-related symptoms, including back and thigh pain, headaches, diarrhoea, nausea and vomiting[1]. Pain commonly starts within three years of menarche[2] and results in life time world-wide prevalence rates ranging from 17–81%[3] with 71% of Australian women suffering from dysmenorrhea in a given year[4]. Primary dysmenorrhea is the most common cause for school absenteeism in women [5] and in 10–30% of women causes regular absence from work, school or university each month [6, 7]. In addition to absenteeism primary dysmenorrhea causes a reduction in academic performance [8, 9], reduced participation in sport and social activities[8] and an overall significant decrease in women’s quality of life [9, 10]. Despite the significant negative impact and disruption to daily living that primary dysmenorrhea has on women most do not seek medical treatment [11, 12].When women do present to their doctor with primary dysmenorrhea, the most commonly prescribed treatments are non-steroidal anti-inflammatories (NSAIDs) and the combined oral contraceptive (COC) pill. These treatments are effective for many women [2, 13], however approximately 25% of women have pain that is refractory to either or both of these standard treatments[14].

Lack of satisfaction in standard treatment leads to an increase in self-care [15, 16], with women commonly using complementary therapies to deal with their menstrual pain[17] in addition to, or instead of, pharmaceutical pain relief, due to a lack of perceived effectiveness[15, 18, 19] or a dislike of using analgesic medication[20]. Surveys of practice show women are presenting to acupuncturists in the community with gynaecological complaints such as primary dysmenorrhea [21] despite the evidence for acupuncture’s effectiveness in treating primary dysmenorrhea being uncertain[22]. Many clinical trials are characterised as having a high risk of bias or a lack of clinical validity due to a significant departure from how acupuncture is delivered in contemporary clinical practice.

Despite the lack of high quality evidence there are plausible mechanisms of action for acupuncture to improve primary dysmenorrhea, including endogenous opioid release[23], reduction of inflammation [24], alterations in uterine blood flow[25] and changes in prostaglandin levels [26]. Acupuncture appears to show a dose response relationship between various needling parameters and pain [27]. There is some evidence that electro-acupuncture provides a more rapid reduction in menstrual pain compared to manual acupuncture; however this finding was based on a single study that used an uncommon style of indwelling acupuncture administered only during menses and assessed using non-validated outcome measures [28]. The timing of treatment around menses has been examined in two studies [29, 30] which suggested that treatment three to seven days prior to menses was more effective than treatment during menses. No previous trials have directly investigated the possible dose response relationship that appears to be present between the use of electro-acupuncture and manual acupuncture or in changing frequency of treatment in a western clinical setting where use of manual acupuncture delivered once per week is more common.

This exploratory study aims to examine the possible impact of changing the mode of acupuncture stimulation and treatment timing on menstrual pain. We hypothesised that both electro-acupuncture and higher frequency of treatment would deliver greater reductions in menstrual pain and greater improvements in health-related quality of life compared to lower frequency or manual acupuncture.

A total of 106 women expressed interest in the study (See Fig 1). Seventy-four women met the eligibility criteria and were randomised to one of the four groups. Sixty-three (85%) women completed the treatment phase of the trial. Ten participants withdrew during the treatment phase of the trial. Withdrawal from the trial was equally distributed across groups, with none of the women citing any group-related concerns as reason for withdrawal.

The demographic and menstrual characteristics of the women at baseline are shown in Table 1. One-way ANOVA and Pearson Chi-square showed three areas of imbalance between the groups at baseline, in SF-36 role physical (F(3,69) = 1.12, p = 0.008), in expectation of benefit (χ(6) = 13.205, p = 0.04) and in current alcohol consumption (χ(3) = 8.562, p = 0.036). These were used as co-variates in the secondary analysis.

However, not all women received all 12 treatments, mostly due to logistical issues around timing of treatments with regards to the start of menses. Twenty-five participants (35.2%) received the full 12 study treatments. The mean number of treatments was 10.6 [95% CI 10.22 to 10.99] for all women who had at least one study treatment. There was no difference in the number of treatments given between groups (F(3,59) = 1.855, p = 0.147).

Table 2 outlines peak pain, average pain, duration of pain and analgesic usage for each of the groups at each time point for adjusted and unadjusted ITT analysis. See S4 File for results of the per-protocol analysis.

Acupuncture treatment, regardless of group, using a manualised acupuncture protocol, showed significant clinical improvements in all menstrual pain scores recorded; ‘peak pain’ over the first three days of the menstrual period and ‘average pain’ over the entire menstrual period, and that reduction was sustained for twelve months. This was supported by a similar significant reduction across all other measures of menstrual impact; duration of pain, analgesic usage, secondary menstrual symptoms and a high self-rated improvement score. Electro-acupuncture did not deliver greater pain reduction than manual acupuncture. Manual acupuncture groups tended to have a higher responder rate, significantly greater reduction in secondary symptoms, and lower analgesic usage. With respect to health related quality of life six domains improved from baseline in the HF groups, with only two improving from baseline in the LF groups. There was no difference between manual and electro-acupuncture in terms of domains improved.

The lack of superiority of electro-acupuncture in terms of pain reduction was unexpected. Electro-acupuncture in the trial was delivered at a 2/100Hz frequency, which has been shown to provide maximal opioid gene expression by combining both high and low frequencies to provide maximal pain relief[46]. This high frequency–low frequency stimulation pattern is very common in gynaecological disorders[47], and is identical to the frequency used in many other trials of electro-acupuncture for primary dysmenorrhea[48–51]. Animal models suggest that needling at REN4, SP8 and SP6, used in 80%, 55% and 98% of all study treatments respectively, regulates neuro-endocrine activities, including levels of progesterone[52]; and needling SP6 has been shown to increase ovarian blood flow via a reflex response in rats[53]. A similar reflex response exists in humans, increasing uterine blood flow by reducing sympathetic activity on vasoconstrictor fibres that innervate the uterus[25, 54]. Uterine blood flow is often reduced in women with primary dysmenorrhea[55, 56] and increasing uterine blood flow appears to be related to some of the analgesic benefits of acupuncture in primary dysmenorrhea[50, 57]. The magnitude of the impact of needling SP6 and, to a lesser extent, REN4 and SP8, may be larger than stimulation-specific differences. Another plausible possibility is that the time course of increased endogenous opioid release caused by electro-acupuncture is too short to contribute to a noticeable overall reduction in menstrual pain [58].

In addition to reductions in pain, many women had a reduction in their secondary menstrual symptoms. Inflammation is a primary cause of primary dysmenorrhea [59] and a possible cause of PMS symptoms, including mood changes, bloating and breast tenderness [60]. The wide range of improvements in both pain and PMS related symptoms, especially mood changes, seen in this trial provide support for acupuncture’s posited anti-inflammatory effects[24], future research including suitable bio-makers would provide more information on these possible pathways.

Analgesic medication usage was lower amongst the manual acupuncture groups. As analgesic usage was allowed ad libitum women may have used analgesic medication to achieve an acceptable level of pain. Therefore, the lower usage of analgesic medication amongst these two groups suggests that without analgesic usage there may have been more pronounced differences between these two groups. The reasons for this lower use are unclear, as electro-acupuncture should provide at least the same amount of relief as manual acupuncture, as the needles were stimulated to obtain DeQi prior to electro-stimulation, thereby delivering a manual acupuncture-like stimulus prior to the addition of the electro-acupuncture pulse[61]. The changes in the HRQoL SF-36 domains suggest that after the course of acupuncture treatment, participants had less problems with work or daily activities as a result of their physical health, less pain and subsequent limitations due to pain, more energy, and less interference from physical and emotional problems in social activities[62], all of which are commonly experienced by women with primary dysmenorrhea [8, 63].

In terms of pain reduction, the trial findings were similar to results provided by previous studies. Direct comparison to studies performed in China[29, 48–51] with very short timescales of measurement post-treatment are problematic as these may not represent meaningful changes over the entire menses. Comparisons with other trials outside of China tend to show similar results to this study. Absolute pain reductions were less than Witt (Germany)[45] and Helms (US) [64] but similar to that found by Smith (Australia)[44]. Comparison with Helms [64] is complicated by the fact that the sample size was very small, showing no between group differences and the use of a custom pain scale that was not validated. The greater absolute pain reduction found by Witt [45] may be due to the nature of the intervention, where physicians were allowed to choose treatment without restriction, or due to the greater sample size, almost ten times the size of this study. However, the responder rates (>30% reduction in average pain from baseline) were similar to Witt’s, showing that the percentage pain reduction from baseline was relatively equal between the two studies. Similarly to Smith [44] and Witt [45], reductions in pain in this study appeared to be sustained or increased after the trial period ended.

There were no between group differences in all pain outcome measures, despite large differences in responder rates between groups. This is most likely due to the exploratory nature of the study, which was not powered to detect small between group differences. A post-hoc power analysis shows that a sample size of 192 would be required to determine a 20% difference between groups for average pain. While a difference of >30% from baseline is considered clinically important, the size of differences between groups that are important to participants appears to be dependent on the condition treated[43]. In this case, these between group differences do not appear to significantly alter how successful women felt their treatment was, supported by the fact there was no difference in self-reported improvement score between groups, however, future studies with significantly more participants would be required to answer this question.

The strengths of this exploratory study were that it recruited a group of participants who were representative of women in the community with dysmenorrhea, having a variety of secondary symptoms, including back pain, fatigue, breast tenderness, nausea, headaches and bowel changes, consistent with many other populations with primary dysmenorrhea[8, 9, 34]. Analgesic usage amongst the study participants was very prevalent (81%), almost identical to the prevalence of analgesic usage in Australian women with dysmenorrhea (80%)[65]. There are several limitations on this exploratory study: Due to the high loss to follow-up at 6 and 12 months the significant use of last observation carried forward in a small sample such as this could contribute to over-estimating the duration of the treatment effect in the intention to treat analysis, however a per-protocol analysis without using last observation carried forward showed similar results. The RCT, due to its design in comparing effectiveness of differing doses of acupuncture, did not have a usual care group. The changes observed over the 12 month period are unlikely to be due to natural reductions in the pain from primary dysmenorrhea[66]. Witt (Germany) [45] showed a 15% reduction in average menstrual pain in the usual care group at 3 months while our study found a 24% reduction in average pain independent of group allocation at the same time point. This suggests an additional benefit of acupuncture but our ability to determine the extent to which acupuncture treatment is responsible for the changes in pain, menstrual symptoms and health-related quality of life observed in the study is limited.

This exploratory study suggests acupuncture administered over three menstrual cycles gave both statistically and clinically significant reductions in menstrual pain compared to baseline and persisted for 12 months, however there was no significant difference in pain intensity between groups. Electro-acupuncture was well tolerated but did not always provide the same magnitude of improvements as manual acupuncture in reducing secondary menstrual symptoms and analgesic medication intake. Manual acupuncture provided the same or greater pain relief as electro-acupuncture, but with less analgesic medication required to achieve this pain reduction. Treatment timing appears to play a small role, with high frequency of treatment providing greater improvements in health-related quality of life. This exploratory trial suggests that there may be an effect of both treatment timing and mode of stimulation, but possibly only of small clinical benefit. Future adequately powered studies are needed to confirm the role of both mode of stimulation and treatment timing and to provide a more accurate indication of the clinical impact of altering these dose components on menstrual pain.