The Comparison of Efficacy of Manual Acupuncture and Laser Acupuncture on Autonomic Nervous Activity and Quality of Life in Women With Dysmenorrhea.
The Comparison of Efficacy of Manual Acupuncture and Laser Acupuncture on Autonomic Nervous Activity and Quality of Life in Women With Dysmenorrhea.
Integrative medicine raises public's attention due to either mainstream or traditional
 medicine has its limitation. Therefore, more and more people are willing to adopt integrative
 in dealing with uncontrollable symptom or disease.

 The topic "dysmenorrhea", with prevalence up to 50%, troubled many females with symptom as
 depression, reduced the quality of life; and even withdraw from daily activity.

 Generally speaking, primary dysmenorrhea is a menstrual pain in the absence of pelvic
 pathology while secondary dysmenorrhea is caused by organic dysfunction such as
 endometriosis, uterus malformation, inflammation, etc. Clinically, gynecologists apply
 analgesic such as Non-steroidal Anti-inflammatory Drugs, and oral contraceptive pills or
 progestin as conventional therapy. As NSAIDs cause gastrointestinal discomfort, while hormone
 therapy leads to other concerns; some women now adopt acupuncture as an alternative therapy
 for its safety. According to the theory of Traditional Chinese Medicine, acupuncture
 regulates meridians' energy whereas the western medicine reveals that the mechanism of
 pain-control of acupuncture is relevant to neurophysiologic and neuroendocrine adjustment.

 Furthermore, laser acupuncture has been practiced in recent years for it integrates the
 meridian theory and laser therapy; hence there are also some positive research in academic
 field. The acceptability of laser acupuncture is much higher than traditional acupuncture for
 its non-invasiveness and could also be practiced by both TCM and western medicine physicians
 in clinics.

 Nevertheless, whether laser or traditional acupuncture is more effective is still under
 debate.

 Additionally, investigators had published that the theory of yin/yang (meridian) is
 compatible with autonomic nerve theory. As many women with dysmenorrhea suffered from
 insomnia, anxiety, convulsion of the uterine muscle, which are related to autonomic nerve
 dysfunction, investigators are intrigued to know whether the effect of acupuncture is related
 to adjusting autonomic nerve system.

 (Aim) Investigators intend to investigate the efficacy of laser and manual acupuncture in
 dysmenorrhea, and whether their mechanism is germane to hormone alternation or autonomic
 nervous system adjustment. The points in this proposal are 1.evaluate the efficacy of
 manual/laser acupuncture in dysmenorrhea in respects of symptoms and quality of life 2.
 compare whether these types acupuncture will alter the prostaglandin or hormone and the
 relationship between with the efficacy. 3. evaluate whether the mechanism of manual and laser
 acupuncture is relevant to alternating the autonomic nerve activity and if not correspond to
 Yin-Yang theory. 4. Determine whether acupuncture will have maintained effect.

 (Method) A three-years, three arms, randomized, controlled, cross-over study will be
 performed to compare the control group, manual and laser acupuncture group. Primary outcome
 measurements include HRV parameters, and serum prostaglandins, estrogen, progesterone in
 different phases; second outcome measurements are VAS, VMSS (dysmenorrhea symptom) score
 analysis and SF12 quality of life assessment in three phases. Investigators expect this
 multidiscipline study could encourage more talk between in TCM and mainstream medicine and
 coordinate the different viewpoints. The study will provide physicians with the evidence
 about manual and laser acupuncture in dysmenorrhea.
1. Background 1.1 The prevalence and mechanism of dysmenorrhea Dysmenorrhea is a troubling
 problem affect more than 50% reproductive-aged women and affect females' quality of life
 is not only physical but also psychologic aspects. It costs a lot of health, social and
 economic burden. The symptom is characterized by cramping pain in the lower abdomen,
 starting within the first eight to 72 hours of menstruation. According to research, the
 severity of dysmenorrhea ranged widely from mild, tolerable to incapability for 1 to 3
 days each menstrual cycle, even incapable of work or daily activity. Some women even
 suffer from autonomic dysfunction symptoms such as dizziness, diarrhea, migraine,
 vomiting, unable to concentrate, negative mood and anxiety or depression. The mechanism
 of pain associated with dysmenorrhea can be addressed by two aspects: neuro-endocrine
 regulated and neuro-physiologic related. One is by the action of prostaglandins such as
 prostaglandin E2, prostaglandin F2α, or vasopressin-related from the endometrium at the
 onset of menstruation which stimulates pain neurons and induces excessive contraction of
 the uterus. Prostaglandin production is controlled by progesterone: when progesterone
 levels drop, immediately prior to menstruation, prostaglandin levels increase. The other
 aspect is that the increasing uterine muscle contractions and hormone secretion is
 regulated by the sympathetic nervous system. Therefore, some scholars stress the
 importance of reducing sympathetic tone or re-imbalance the autonomic nervous activity.
 Accordingly, investigators note that some research such as yoga, or aerobic exercise
 applied in dysmenorrhea are designed through this approach.

 1.2 Current treatment of dysmenorrhea The conventional treatments adopt the use of
 non-steroidal anti-inflammatory drugs (NSAIDs) combined with oral contraceptives or
 progestins. Hormonal contraceptives are the first-line treatment for dysmenorrhea caused
 by endometriosis. Topical heat, exercise, and nutritional supplementation may be
 beneficial in patients who have dysmenorrhea. The NSAIDs may induce gastrointestinal
 disturbance while the hormone treatment may increase the risk of some cancer or other
 heart problems; therefore, around 25% of patients are refractory to conventional
 therapy. Some women choose alternative therapies such as yoga, acupuncture, or massage
 for relieving their pain albeit the evidence of these therapies is not enough.

 1.3 The role of acupuncture in dysmenorrhea Acupuncture, which is non-invasive and with
 few side effects; has been proved with well anesthetic effect in pain control through
 varied mechanisms. On one hand, some study propose that the mechanism of acupuncture in
 dysmenorrhea is based on changes in neurophysiologic and neuro-hormonal activities such
 as endogenous opioid, serotonin, and acetylcholine which results in pain reduction; on
 the other hand, some study indicate that acupuncture has an effect in the reduction of
 inflammation, alterations in uterine blood flow and changes in prostaglandin levels.
 Previous research confirmed that acupuncture affects the autonomic status to some extent
 in diverting circumstances, yet the style of acupuncture varied from manual to warm to
 laser acupuncture etc. In addition to pain relieving, acupuncture has been reported with
 the efficacy in improving the quality of life and decreasing NSAID use after regular
 treatment for 3 to 6 months.

 1.4 manual acupuncture VS Laser acupuncture Laser acupuncture raises the public's
 attention for its much less invasive than real acupuncture. In previous time, only TCM
 doctors or acupuncturists could practice the acupuncture; yet since laser acupuncture is
 not invasive, mainstream (western medicine) physicians could also practice laser therapy
 in the clinic, more and more research about laser acupuncture was published in the field
 of pain control, orthopedics, and internal medicine. Nevertheless, the research
 regarding laser acupuncture applied in dysmenorrhea is rare, only one trial is noted in
 the Pubmed, which intrigues us to further investigate the potential effect of laser
 acupuncture in dysmenorrhea now that investigators already have abundant manual
 acupuncture experience in this issue. Additionally, it is believed that acupuncture
 could attenuate pain or improve microcirculation by regulating the autonomic nervous
 system. However, whether the effect of manual and laser acupuncture on autonomic nerve
 activity is the same is still controversial. Some study indicates laser acupuncture
 could be an alternative stimulate therapy for it has the same effect as manual
 acupuncture on vagal activity whereas still, other studies note laser acupuncture has a
 different effect from manual acupuncture on autonomic activity. As a result,
 investigators aim to know more about these two types acupuncture's effect on HRV and
 compare their effectiveness.

 1.4.1 The theory of manual and laser acupuncture While manual (Traditional) acupuncture
 has been well studied for its mechanism, which was postulated as relating to a
 neurophysiologic pathway or neuroendocrine adjustments, such as increasing endorphin,
 substance P and other pro-inflammation cytokines; the mechanism of laser acupuncture
 might be different yet is as effective as manual acupuncture. In some study, laser
 acupuncture is proved with improving microcirculation, whereas others supposed it also
 has an anti-inflammatory effect. Previous research revealed that laser therapy could
 attenuate the cholinergic hyperreactivity and regulate NF-kappa-B activation. Wang et al
 in 2017 also stated that laser acupuncture has an effect on Heart Rate Variability of
 patients with spinal cord injury.It is supposed the meridian system is similar to the
 sensory nervous system and the laser acupuncture has an effect on HRV through this
 system. This finding strengthens the theory investigators proposed before, revealing
 that the theory of the meridian system is an analog to nerve system. In this context,
 investigators hypothesize that both manual and laser acupuncture has an effect on the
 meridian system as well as the autonomic nervous system yet need further trial
 investigation.

 1.5 Prospective of laser acupuncture in dysmenorrhea As many females troubled with the
 dysmenorrhea and hormone or analgesics therapy has a certain effect, acupuncture is
 promising for its less-invasiveness. Furthermore, if laser acupuncture is non-inferior
 to manual acupuncture or even much more effective; then it could be another alternative
 therapy in this issue. Both doctors in TCM or western medicine fields may also adopt
 them in outpatient clinics.

 1.6 The correlation of Meridian system and Autonomic system in acupuncture study In
 recent decades, more and more researchers demonstrated that the meridian system
 corresponds to the nervous system or has some overlapping with it. The study indicated
 that stimulating some acupoints or meridians could change the autonomic activity and
 attain the goal of improving some physiologic problem. Chien et al in 2014 indicated
 that acupoints stimulation could modulate the autonomic nervous system to exert its
 physiological effect through the pathway of the meridian system. Cui et al revealed that
 stimulating Heart Meridian may improve AMI by inhibiting sympathetic discharges and
 elevating vagal discharges in AMI rats. These studies confirmed the relationship between
 meridian and autonomic system, yet few studies compare the efficacy or mechanism of
 different treatments (medication or different types acupuncture) in applying in the same
 disease. That is why investigators intend to apply two different acupuncture (manual and
 laser) to compare their effect on autonomic nervous system and efficacy in clinics.

 1.7 Autonomic nerve activity V.S manual/ laser acupuncture V.S dysmenorrhea As has
 mentioned, acupuncture works through regulating yin-yang and meridian energy. The
 interesting thing is that from our previous study, investigators found that the concept
 of parasympathetic/sympathetic system is compatible with yin/yang theory in Chinese
 Medicine to a certain extent; while the promotion of energy is consistent with the
 "De-Qi" in performing acupuncture. Since the symptoms related to dysmenorrhea such as
 pain, diarrhea, headache, poor sleep are also related to autonomic dysfunction.
 (imbalance of sympathetic/parasympathetic tone); investigators are intrigued by whether
 the mechanism of acupuncture is relevant to the improvement of autonomic nerve activity
 in dysmenorrhea. Do the manual and laser acupuncture work through the same mechanism on
 autonomic nerve system or meridian network? Accordingly, under the context that
 acupuncture might have an effect on reconciling the autonomic nervous imbalance and
 yin/yang in dysmenorrhea and to further understand this issue, investigators intend to
 compare the manual, laser acupuncture and conventional treatment reflecting in autonomic
 nervous activity and effect on dysmenorrhea.

 1.7.1 The clinical meaning of parameters in measure Autonomic nerve activity So far,
 researchers have a consensus in adopting HRV measurement to monitor the autonomic nerve
 activity. Several parameters include frequency domain and time-domain analysis. To
 differentiate the sympathetic and parasympathetic tone, most of the studies acknowledge
 that HF power as an index of parasympathetic activity; LF power as an index of both
 parasympathetic and sympathetic activation and suggests the measure of LF/HF as an index
 of "autonomous balance". In the time domain, the standard deviation of normal RR
 intervals (SDNN), the root mean square successive differences (RMSSD) and the percentage
 of adjacent cycles that are greater than 50 ms (pNN50) are considered as indices of
 vagal activity. As for the HRV (Heart rate variability), which is viewed as a phenomenon
 of the flexibility of the autonomic nervous system, SDNN and TP were found to represent
 total HRV activity as well, especially in discussing the relationship with health.
 Accordingly, when pain or symptoms were mitigated, the parasympathetic related
 parameters will elevate or the ratio of LF/HF will change in favor of HF. And for
 improving tolerance of the pain or decrease of the pain threshold, the HRV and SDNN, TP
 will increase thereby. Investigators, therefore, apply these changes to monitor the
 effect of acupuncture on dysmenorrhea.

 1.8 The relationship of hormone and dysmenorrhea Previous research noted that the
 dysmenorrhea may be caused by the overproduction of uterine prostaglandins (PGs), which
 might be regulated by progesterone, though not totally depend only on endocrine factors.
 All women have increased levels of PGs during the luteal phase compared with the
 follicular phase of ovulatory cycles. However, compared with eumenorrheic women,
 dysmenorrhea women have higher levels of PGs and the concentration of progesterone per
 menstruation was significantly higher in the eumenorrheic women than in the dysmenorrhea
 patients as well. Some gynecologists even use prostaglandin synthetase inhibitor ( ex.
 Ibuprofen) in dealing with the dysmenorrhea. The shift of estradiol/progesterone ratio
 in favor of estradiol contributes to the underlying pathogenic principle of
 dysmenorrhea. Therefore, the change of hormones, including estradiol, progesterone and
 prostaglandin could present the level of improvement of dysmenorrhea.

 2. Previous related study 2.1 Acupuncture applied in dysmenorrhea From research,
 acupuncture is very popular when it comes to some gynecologic problems, such as
 menopause symptoms or premenstrual syndrome. However, most study focus on the comparison
 of acupuncture and sham acupuncture or NSAID and the acupuncture protocol is not
 conclusive; some chose only one acupoint (SP6) while others chose a group of acupoints.
 So far, none of the studies compares the efficacy and effect on HRV or changes on
 hormone and prostaglandin between in manual and laser acupuncture.

 2.2 Heart rate variation (HRV) VS Cytokine and Acupuncture Regarding the connection of
 acupuncture and autonomic nerve system or Heart rate variation (HRV), Acupuncture is
 hypothesized to modulate the neuroendocrine and autonomic nervous system and thereby
 revitalize the balance of metabolism in the body. Investigators noted some evidence
 confirmed that acupuncture could improve depression, fatigue through regulating cytokine
 and autonomic nervous system. Nevertheless, whether there will be any relationship
 between the cytokine change and HRV activity is uncertain. As a result, the study is
 designed for checking the correlation of change in cytokine (Prostaglandin, estrogen,
 progesterone) and HRV activity in dysmenorrhea beyond the evaluation of comparing
 efficacy. Investigators suppose the phenomenon of decreased prostaglandins and increased
 progesterone will be noted in dysmenorrhea patients benefit from acupuncture.

 3. The prospect of this study The study investigators design not only aim to compare the
 efficacy of manual, laser acupuncture and control group in dysmenorrhea but also further
 investigate whether their effect on HRV is different. The acupoints investigators chose
 are most located in Yin meridians which correspond to Yin-Yang theory that " Yang
 masters Chi while Ying masters blood "and "Yang is frequently in excess while yin is
 often in deficiency". Investigators aim to reconcile the yin-yang through the special
 designed acupoints protocol. Additionally, investigators can also confirm whether the
 effect of manual and laser acupuncture in dysmenorrhea is related to the improvement of
 autonomic nerve activity and try to integrate our understanding about neurophysiology
 and acupuncture along with TCM-Yin/Yang theory based on the previous study. Whether
 acupuncture could change the hormone peptides or cytokine would be evaluated to clarify
 the mechanism of how manual or laser acupuncture work. Investigators expect the study
 can promote the crosstalk between the Chinese and western medicine and provide more
 definitive evidence for acupuncture applied in dysmenorrhea.

 4. Objective and approach Investigators design a three-arms clinical randomized study,
 which includes manual acupuncture, laser acupuncture and conventional therapy (NSAIDs
 and OCP) and enrolls women with dysmenorrhea.

 5. Specific Aims Specific aim 1: To compare the efficacy of manual and laser acupuncture
 and control group (conventional therapy: including NSAIDs) in dysmenorrhea.

 Specific aim 2:To evaluate whether the laser and manual acupuncture will affect the serum
 prostaglandin, and hormone (progesterone and estradiol) and the relationship between with the
 efficacy in dysmenorrhea.

 Specific aim3: To identify the relationship between autonomic nerve activity change and laser
 / manual acupuncture reflect in dysmenorrhea and integrate with the TCM -Yin/Yang and
 meridian theory.

 Specific aim4: To identify whether laser or manual acupuncture has maintained effect after
 one month wash-out phase.
Inclusion Criteria:

 1. Women within reproductive age (15 to 49 years);

 2. Participants who complain about dysmenorrhea with at least grade II level.

 3. Self-reported lower abdominal and pelvic, medial anterior thigh pain or low back pain
 associated with the onset of menses and lasting in 72 hours.

 4. Some accompanied symptoms as dizziness and syncope, cramping, nausea, vomiting,
 diarrhea, headaches, and fatigue present compatible with the menses cycle were also
 included.

 Exclusion Criteria:

 1. Dysmenorrhea resulting from the use of an intra-uterine device (IUD);

 2. Mild or infrequent dysmenorrhea.

 3. Dysmenorrhea with possible underlying tumor or malignancy