BMJ Acupuncture point injection treatment of primary dysmenorrhoea

7/23/2019 BMJ Acupuncture point injection treatment of primary dysmenorrhoea

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Acupuncture point injection treatmentof primary dysmenorrhoea:a randomised, double blind,

controlled studyC Wade,1,2 L Wang,3 W J Zhao,3 F Cardini,4 F Kronenberg,1,5 S Q Gui,3 Z Ying,6

N Q Zhao,7 M T Chao,1,8 J Yu3

To cite:Wade C, Wang L,

Zhao WJ,et al. Acupuncture

point injection treatment of

primary dysmenorrhoea:

a randomised, double blind,

controlled study. BMJ Open

2016;6:e008166.doi:10.1136/bmjopen-2015-

008166

Prepublication history for

this paper is available online.

To view these files please

visit the journal online

(http://dx.doi.org/10.1136/

bmjopen-2015-008166 ).

Received 13 March 2015

Revised 25 November 2015

Accepted 26 November 2015

For numbered affiliations see

end of article.

Correspondence to

C Wade;

[email protected]

ABSTRACTObjective:To determine if injection of vitamin K3 inan acupuncture point is optimal for the treatment ofprimary dysmenorrhoea, when compared with 2 other

injection treatments.

Setting:A Menstrual Disorder Centre at a publichospital in Shanghai, China.

Participants:Chinese women aged 1425 years withsevere primary dysmenorrhoea for at least 6 monthsnot relieved by any other treatment were recruited.

Exclusion criteria were the use of oral contraceptives,intrauterine devices or anticoagulant drugs, pregnancy,history of abdominal surgery, participation in other

therapies for pain and diagnosis of secondarydysmenorrhoea. Eighty patients with primarydysmenorrhoea, as defined on a 4-grade scale,

completed the study. Two patients withdrew afterrandomisation.

Interventions:A double-blind, double-dummy,randomised controlled trial compared vitamin K3acupuncture point injection to saline acupuncture pointinjection and vitamin K3 deep muscle injection.Patients in each group received 3 injections at a single

treatment visit.

Primary and secondary outcome measures: Theprimary outcome was the difference in subjectiveperception of pain as measured by an 11 unit Numeric

Rating Scale (NRS). Secondary measurements wereCox Pain Intensity and Duration scales and theconsumption of analgesic tablets before and after

treatment and during 6 following cycles.

Results:Patients in all 3 groups experienced painrelief from the injection treatments. Differences in NRSmeasured mean pain scores between the 2 active

control groups were less than 1 unit (0.71, CI1.37to0.05) and not significant, but the differences inaverage scores between the treatment hypothesised to

be optimal and both active control groups (1.11, CI0.45 to 1.78) and (1.82, CI 1.45 to 2.49) werestatistically significant in adjusted mixed-effects

models. Menstrual distress and use of analgesics werediminished for 6 months post-treatment.

Conclusions:Acupuncture point injection of vitaminK3 relieves menstrual pain rapidly and is a useful

treatment in an urban outpatient clinic.

Trial registration number: NCT00104546;Results.

INTRODUCTIONDysmenorrhoea is highly prevalent and amajor cause of activity restriction and school

absence among young women worldwide.1 2

Primary dysmenorrhoea is a painful men-strual cramping of the uterus without identi-able organic pathology that affects as manyas 85% of women, 20% of whom describetheir pain as severe.3 4 The initial onset ofprimary dysmenorrhoea is usually shortlyafter menarche, 612 months after ovulatorycycles begin. High levels of uterine prosta-glandins, a hormone associated with uterinecramping, abdominal pain and contractionof muscular tissue, have been identied as asubstantial contributing factor to the pain

Strengths and limitations of this study

The results of this trial document the efficacy ofa treatment in use for over 40 years at a high-volume Menstrual Disorder Centre and provide

important information about a treatment for acommon condition of women worldwide.

The design is rigorous: a double-blind, double-

dummy, randomised controlled trial powered tocompare three active treatments.

The primary outcome effect size of the differencebetween groups is robust.

Owing to funding limitations, the study wasimplemented in two phases under two differentrandomisation schemes and data from the first

phase were analysed prior to the implementationof the second phase.

Stratified analyses were conducted to account for

any differences between the results of the twophases of the trial.

Wade C,et al.BMJ Open2016;6:e008166. doi:10.1136/bmjopen-2015-008166 1

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and distress that are the major symptoms of dysmenor-rhoea.5 6 The pain duration is commonly 872 h and isusually associated with the onset of menstrual ow.1

The condition often results in activity restriction over13 days of each menstrual cycle,3 and therefore theannual costs in terms of disability, in addition to treat-ment, are high.

The two most common treatments in the USA for dys-

menorrhoea are non-steroidal anti-inammatory drugs(NSAIDs) and oral contraceptives (OCs).7 NSAIDs areeffective for some but not all women, with a failure rateof up to 25%.8 Both treatments require multiple or dailydosing and have side effects. In China, common treat-ments for dysmenorrhoea include acupuncture andherbal preparations, with increased use of NSAIDs inrecent years; OCs are seldom prescribed for thecondition.

Injection of an agent, usually a herbal extract or drug,into an acupuncture pointisan innovation in TraditionalChinese Medicine (TCM)6 9 and has been used in China

over the past 40 years.

10

Classical and modern acupunc-ture usually involves needles inserted at multiple pointsand left in place for 2060 min. In contrast, acupuncturepoint injection is easily administered and standardised,and requires less time at the clinical encounter.11

Acupuncture point injection of vitamin K3 has beenused as a standard of care treatment for dysmenorrhoeaat the Menstrual Disorder Centre at the Obstetrics andGynecology Hospital in Shanghai, Peoples Republic ofChina, since at least 1985,12 and several uncontrolledstudies of the treatment have been conducted inChinaand Italy with various forms of vitamin K.1315 Whilevitamin K3 has been administered consistently at the

clinic where this study was conducted,16 this form ofvitamin K is not typically used in the USA and Europe.Vitamin K1, however, is routinely administered to new-borns shortly after birth to augment coagulation and isconsidered to be safe. A pilot study of the acupuncturepoint injection treatment with a cross-over design substi-tuted vitamin K1 for vitamin K3 and explored theacceptability of the treatment in the USA and theabsorption of vitamin K1.17 18

While the positive results of these prior studies arepromising, it was unknown whether vitamin K as anagent and the acupuncture point as the site of injection

were essential to the treatments effect and whether

together they were an optimal treatment for pain reliefof primary dysmenorrhoea as compared with otherinjection treatments. To address this question, theprimary objective of this study was to compare: (1) theeffects of vitamin K injection in a non-acupuncturepoint, (2) the effects of injection of a non-active sub-stance in the acupuncture point, and (3) the combinedeffects of vitamin K injected in the acupuncture point.In addition, we sought to evaluate whether the treat-ments, given only once, relieve menstrual pain at avariety of time points; and to evaluate the feasibility ofconducting an international randomised trial with a

comparative effectiveness design. Our secondary out-comes were whether the treatments administered in asingle cycle had a carryover effect and decreased men-strual pain, distress and the need for medications oversix cycles.

MATERIALS AND METHODS

Written informed consent was obtained from youngwomen, and assent and parental consent from girls andtheir families. The study was conducted in accordancewith the requirements of Good Clinical Practice.We conducted a double-blind, double-dummy, rando-mised controlled trial with three parallel groups:

Group A saline acupuncture point injection: Study partici-pants randomised to this group received normal salineinjection at the San Yin Jiao or Spleen 6 (SP6) acu-puncture point (both legs) and saline in the rightbuttock. This served as an active control for vitamin K.Group B vitamin K deep muscle injection: Study partici-

pants randomised to this group received a vitamin K3injection in the right buttock and saline at a non-acupuncture point near but not SP6 (both legs). Theclinicians located the sham point at 1 cm above Sp6,1 cm towards the back of the leg from Sp6, and pene-trated the needle 1 cm beneath the skin. This served asan active control for the acupuncture point injectionsite and ensured that the patients in this group hadthe same dose of vitamin K3 as group C, albeit at a dif-ferent injection site.Group C vitamin K acupuncture point injection: Study parti-cipants randomised to this group received a vitamin K3injection at the SP6 point (both legs) and saline in the

right buttock. A third injection of saline in the buttockwas administered to maintain uniformity of treatmentwith groups A and B.

The treatments were administered only once.The alternative hypothesis to all treatments having

similar effects on pain of primary dysmenorrhoea is thatpain relief in group Cthe treatment most closelyaligned with TCM theory and clinical innovations at theMenstrual Disorder Centrewas optimal compared withthe other two treatments.

Young Chinese women aged 1425 years with severeprimary dysmenorrhoea for at least 6 months that had

not been relieved, or only partially relieved, by any othertreatment were recruited for this study. A four-gradescale which grades dysmenorrhoea as absent, mild, mod-erate or severe based on the presence of cramps,whether or not the cramps were very painful or causedpatients to sometimes or always cut back on activities,19

was used to screen prospective participants to determineeligibility. Young women enrolled in the study were nul-liparous, Mandarin or Shanghainese speaking, withregular menstrual cycles for the past 6 months, and whohad a working phone.

Exclusion criteria were diagnosis of secondary dysmen-orrhoea, the use of OCs, intrauterine devices or

2 Wade C,et al. BMJ Open2016;6:e008166. doi:10.1136/bmjopen-2015-008166

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anticoagulant drugs, pregnancy, history of abdominalsurgery, participation in other therapies for acute orchronic pain and diagnosis of dysmenorrhoea due toany recognised cause, such as pelvic inammatorydisease. In addition, women who had had previous injec-tion treatment with vitamin K in SP6 for any reason orwho were intolerant to NSAIDs or who planned to beout of the area during the course of the 7-month study

were excluded.Study participants were recruited from patients who

presented with pelvic pain at the Menstrual DisorderCentre at the Obstetrics and Gynecology Hospital,Fudan University, in Shanghai, China. Information ses-sions were conducted at Fudan University to let youngwomen and providers know about the study at the clinic.Study physicians and staff screened prospective womenand girls for eligibility and interest, described the studydetails and obtained consent. For women under the ageof 18, parental consent was also obtained. Diagnosis ofprimary dysmenorrhoea was conrmed by the study phy-

sicians on the basis of history and physical examination.Prospective participants who were not currently in painsigned consent forms and were told to return at theonset of their next painful menstrual cycle. Participantscould also consent and receive the treatment on theirinitial visit if they were currently in pain due to menses.Participants were informed that they could withdrawfrom the study at any time.

Treatments were administered only once by medicaldoctors who were also experienced acupuncturists. Painmeasurement was conducted by clinic staff and not thestudy physicians. Participants were followed for 6 monthswith follow-up phone interviews by clinic staff.

Treatment consisted of an injection at each of three sitesas per group assignment. A single injection of vitaminK3 is 4 mg/mL, so since participants were injected oncein each leg, the total dose was 8 mg of vitamin K3 or2 mL of saline solution. The SP6 acupuncture point islocated on the lower leg, 3 cun or four widths of themiddle phalange of the index nger on the patient,proximal to the peak of the medial malleolus, just alongthe posterior aspect of the tibial bone. The muscleinjected was m. soleus (see gure 1). An injection of8 mg of vitamin K3 or 2 mL saline (depending on thegroup) was administered as a deep intramuscular injec-

tion in the glutaeal muscle of the right buttock. NSAIDswere available in case any patient was not satised withpain relief from the treatment after 1 h.

Vitamin K3 was used because it is and has been theagent used in the Menstrual Disorder Centre at theObstetrics and Gynecology Hospital for treatment ofprimary dysmenorrhoea. Vitamin K3 ampoules were pre-pared by the Shanghai #1 Biochemical andPharmaceutical Company, Ltd. The investigators visitedthe company in January 2004 to specify a design forblinding (packaging, coding and labelling) of theampoules. Vitamin K3 and saline ampoules looked iden-tical. The injection site was specied on the ampoules.

The randomisation list was created by a biostatistician,who went to the certied research pharmacy, whichencapsulated the agents to blind the treatment and thensent the ampoules to the research site. Eligible consent-

ing participants were assigned to a group at the treat-ment visit according to a randomly permuted blockdesign with blocks of size 6 to ensure equal allocation ofpatients to each treatment group. The randomisationscheme was generated and held by the studybiostatisticians.

Physicians were blinded as to saline and vitamin K3,but they knew whether they were injecting into the acu-puncture point or near the acupuncture point. Thus,study physicians knew when they were administering togroup B, but they could not differentiate the treatmentsin groups A and C. Patients presumably did not know

the difference between the acupuncture point and nearthe acupuncture point and were blinded as to the agentin all three groups. Evaluators (study staff collectingpain measures and other study data) did not know thegroup assignment of participants.

Baseline data were collected following consent andprior to treatment. The primary outcome, change inpain intensity at 0 and 60 min, was recorded on an11-unit Numeric Rating Scale (NRS) from 0 to 10 with 0being no pain and 10 being the worst pain the partici-pant could imagine. Pain scores were obtained at base-line and at 2, 5, 30 and 60 min post-injection. Asecondary outcome was the consumption of analgesic

Figure 1 In two of the groups injections were in the Spleen

6 (SP6)/San Yin Jiao (SYJ) acupuncture point near the ankle

on both legs. In the third group the injection site was near but

not on SP6.

Wade C,et al. BMJ Open2016;6:e008166. doi:10.1136/bmjopen-2015-008166 3

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tablets during the menstrual cycle before and after theinjection treatment. Menstrual-related symptoms, suchas hours in bed and time lost from school or work, wererecorded at baseline and after treatment. Participantsmenstrual distress was evaluated after each menstrualcycle on two different scales: Cox RetrospectiveSymptom Scale (over 6 cycles) and Moos MenstrualDistress Questionnaire (MMDQ) (over 2 cycles).20 21

The Cox scale included 17 symptoms commonly asso-ciated with menstrual distress. Each of these was rated bythe participant on both intensity and duration with arange from 0 (not perceptible) to 4 (extremely upset-ting). The MMDQ assessed six symptoms: muscle stiff-ness, headache, cramps, backache, fatigue and generalaches and painseach on a range of 0 (not present) to4 (severe). A questionnaire to assess patients expect-ation about group assignment and attitude towards par-ticipation in the research study was also administered.

The trial was conducted in two phases. The rst phasewas conducted as an exploratory pilot with 12 partici-

pants randomised to each of the three groups. Theresults of the pilot were positive, with the effect size forgroup C exceeding the hypothesised clinical effect whencompared with the other groups. For the second phase,the investigators conducted a power calculation basedon the effect sizes of the primary outcome from thepilot phase. Using a Bonferroni correction for multipletesting, we estimated that with 26 patients in each group,we could detect change in mean pain scores of 2 unitswith SDs of 2.0 between groups at =0.05 and 95%power. A stratied analysis was planned to accommodatethe two phases of the randomised study.

Continuous variables were summarised by descriptive

statistics: mean, SD, median and range. Categorical vari-ables were summarised in terms of frequencies and per-centages and groups were tested to see if they differedon population characteristics. Initially, results from thetwo phases of the trial were tested in stratied analyses,however, the results were parallel and homogeneouswith no signicant difference between the stratied andunstratied results, so the data were then combined inthe analysis for reporting. Treatment differencesbetween the three groups were compared both inmarginal-effect and mixed-effect models using Stata V.11(College Station, Texas, USA). A linear mixed-effects

model was applied for the primary outcome, where painscores at time 0 (baseline) and 60 min were the tworesponse variables (per participant), each of which hadits own interceptor representing the average pain levelat that time point.22 23 The observed covariates weretreatment modalities and each individual was assignedwith an unobserved random effect. The treatment effectis the difference at the 60 min time point between thetwo arms under consideration. Signicance levels wereobtained and adjusted for multiple comparisons usingScheffe and Tukey-Kramer methods.22 Analysis of vari-ance (ANOVA) was used to compare mean differencesboth (1) BETWEEN and (2) WITHIN groups on the

secondary outcomes of the Cox and MMDQ scores forcycles 1 and 2 and also for cycles 1 and 7.

RESULTSBaseline dataThe study initiated in October 2004 and ended in June2010. Phase I was completed in 2 years as it was National

Institutes of Health (NIH) funded and physicians hadrelease time to conduct the study: phase II took fouradditional years to complete. Young Chinese women pre-senting with severe pelvic pain to an urban hospitalclinic who were willing to be randomised to active treat-ments were screened for eligibility and signed consentforms. The parents of girls under 18 also consented tohave their children participate. Of the 124 womenscreened, 82 enrolled in the study and were randomised,80 of whom completed all study visits (see gure 2). Twowomen withdrew after they signed consent forms andwere randomised, because they or their parents changed

their minds about participation in a research study. Thebaseline demographic characteristics and menstrualcycle proles of the women did not differ between thethree groups (seetable 1).

Reduction of pain: When treated with an acupuncturepoint injection of vitamin K3 in SP6 (group C), partici-pants had an average 6.6 point decrease in pain on theNRS ( from 8.0 to 1.5, p


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not observed between groups (cycles 1 and 2 and cycles1 and 7) on the Cox Duration and Intensity measures. Asignicant difference however ( p


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indicated that they did not know which treatment theyreceived (68.8% and 57.5%) and the majority of theremainder thought they had received injection at thetrue acupuncture point (30.0%) as well as vitamin K3(36.3%). Only a small proportion thought they hadreceived a control treatment: 1.3% thought they hadreceived an injection near the acupuncture point and6.3% thought they had received saline. These resultssuggest that the blinding procedures were effective.

DISCUSSIONAll three active treatments reduced menstrual cycle painrapidly (within an hour) with minimal side effects, but

acupuncture point injection with vitamin K3 in SP6 wasfound to be optimal, producing a greater clinical andstatistically signicant reduction in pain. One to twounits on the NRS for pain has been described as clinic-ally signicant by studies designed to evaluate unitscores with clinical improvement.24 25 Acupuncturepoint injection with vitamin K3 provided rapid relief ofsevere as well as moderate pain due to dysmenorrhoea.Effective treatment can be administered in a high-volume hospital clinic and may be especially useful towomen whose pain is unmitigated by other methods. No

differences between groups were found on long-termeffects, but at the end of the study, participants in allactive treatment groups endured signicantly less painover a reduced duration and reported fewer activityrestrictions, fewer hours in bed and the consumption offewer drugs for menstrual pain over the course of sixcycles than at baseline, indicating the value of injectiontreatments for primary dysmenorrhoea. All three treat-ments reduced pain rapidly during the treatment cycle,yet the treatment in standard use at the clinic, injectionof vitamin K3 in SP6, was clearly more effective than theother two treatments on the primary short-termoutcome.

The pattern of reduction of menstrual distress overthe follow-up cycles is consistent. Women in all of thetreatment groups experienced long-term relief.Differences between the three groups on the secondarylong-term outcomes of menstrual distress were not sig-nicant. Patterns of analgesic use may interact withscores of menstrual distress. In this study, group B, forexample, consumed more analgesics than the other twogroups. Future research should take this into accountwhen building analytic models. The sensitivity of theCox and MMDQ scales over the long follow-up period is

Figure 3 Pain intensity at

baseline and in the first hour after

treatment (SP6, Spleen 6).

Table 2 Pain intensity at baseline and in the first hour after treatment

Overall model F-value=14.47 (p


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unknown. Both instruments were administered with theidea of validating results from one to the other anddetermining the best instrument for future research.The MMDQ scale may be more sensitive than the Coxscale for long-term follow-up assessment.

The overall reduction of menstrual distress and thedecrease in the need for analgesics across groups duringthe follow-up period is notable. Whether these effectsare due to the treatment or to the natural course of dys-menorrhoea over 6 months is unknown, but meritsfurther study. Differences between the effects of thethree treatments on menstrual distress in subsequentcycles were more variable than the short-term painoutcome and may be obscured by the use of pain medi-cations and other home remedies which participantswere free to employ during the long follow-up period.

The three-arm study was designed to control for mul-tiple effect pathways, and therefore the results supportthe injection site (an acupuncture point) as a crucial

aspect of optimal pain relief. Little information existsabout any specic mechanism of acupunctures effect onmenstrual pain, and while acupunctures interruption ofpain pathways has been investigated since 1979,26 muchremains unknown about the cause and magnitude of theeffects of acupuncture, as placebo-controlled trials ofmanual treatments are difcult to evaluate. Many studiesof acupuncture do not nd signicant difference ofeffects for off-point and on-point stimulation with acu-puncture needles.27 28 Point injection may have differenteffects than classical acupuncture, and measurement ofoutcomes may not have been sensitive enough in someprevious studies to determine optimal effects.29 Benetsof acupuncture point injection may include rapid andsubstantial pain relief and prolonged effects across avariety of pain conditions.3032 The three injection treat-ments administered in this study worked rapidly,perhapsquicker than NSAIDs, which optimises at 12 h,33 34 andour study indicates that the treatment may have long-term

Table 3 Menstrual distress before and after injection treatment and during follow-up cycles

Cox duration* Cox intensity* MMDQ*

Daily activity

restriction

Increased

hours in bed

Study period Mean Mean Mean Per cent Mean SD

Baseline cycle 1

Group A (control for vitamin K) 1.42 1.19 1.20 96.30 6.52 3.95

Group B (control for point location) 1.40 1.18 1.38 100.00 6.67 4.26

Group C (standard) 1.29 1.18 1.34 100.00 7.58 5.38Treatment cycle 2

Group A (control for vitamin K) 0.84 0.68 0.69 59.26 3.60 1.35

Group B (control for point location) 0.93 0.68 0.82 74.07 5.40 2.80

Group C (standard) 0.83 0.69 0.69 61.54 4.57 1.81

Cycle 3

Group A (control for vitamin K) 0.85 0.66 n/a 65.38 4.33 1.30

Group B (control for point location) 0.93 0.76 n/a 62.96 5.00 1.85

Group C (standard) 0.73 0.57 n/a 50.00 5.13 2.47

Cycle 4




Cycle 5

Group A (control for vitamin K) 0.77 0.52 n/a 42.31 7.67 5.99Group B (control for point location) 0.78 0.66 n/a 55.56 5.11 1.76


Cycle 6




Cycle 7




*Although all three groups experienced reduction in menstrual distress on the Cox and MMDQ scales between baseline and cycle 2 andbetween baseline and cycle 7, the only significant difference in group means was on the MMDQ scale between baseline and cycle 2.Standard treatment at the Menstrual Disorders Centre, Obstetrics and Gynecology Hospital, Shanghai.Significant difference (p


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effects on menstrual distress of up to 6 months. An effectof up to 3months has been observed in at least one previ-ous study.14 Although this treatment cannot be self-

administered, it does not require dosing prior to theonset of worst symptoms, as NSAIDs do, and nor does itrequire daily dosing as OCs do.

Our results also indicate that vitamin K3 may havesome role in amelioration of menstrual pain, althoughthe mechanism is as yet unclear, as none of the forms ofvitamin K are known to have analgesic effects. At leastone form of vitamin K is absorbed through this treat-ment: increased concentrations of vitamin K1 (phyllo-quinone) following injection at SP6 were observed in astudy of four participants with primary dysmenor-rhoea.18 Analysis of plasma phylloquinone indicatednon-detectable concentrations before acupuncture point

injection with vitamin K1, which increased up to425 nmol/L, 2048 h following injection. The vitamin Kprole of women with menstrual cycle disorders may beworth exploring in a nutritional approach to dysmenor-rhoea prevention.

The use of vitamin K3 (menadione) for this treatmentis routine at the Menstrual Disorder Centre at theObstetricsand Gynecology Hospital where this study wasconducted.1 4 1 6 Studies in the USA and Europe havetested alternate forms of vitamin K. Vitamin K1 (phyl-loquinone) and K4 (menaquinone-4) were chosen overvitamin K3 because of availability in the clinical setting

and becausevitamin K1 has a better safety prole thanvitamin K3.35 These studies also found that menstrualpain and distress were relieved.14 15 17 Little is knownabout vitamin Ks role in ameliorating symptoms of dys-menorrhoea or difference in effect in the administrationof the various forms of vitamin K. NSAIDs alleviate thepain of menstrual cramps through their effect on prosta-glandin levels. One study that measured prostaglandinlevels after acupuncture using the point SP6 did notnd that the treatment reduced them.6 To the bestof our knowledge, studies of vitamin K and prostaglan-din levels have not been reported. However, vitamin Kis being explored for its potential role in reducing

proinammatory cytokines.36 Vitamin K is typically usedclinically to abet blood clotting and, recently, has beenstudied in relation to bone health. Animal studies haveshown that ovary concentrations of vitamin K are higherthan in other organs,37 and researchers have suggestedthat vitamin K may play a role in reproductiveendocrinology.38

Our overarching goal was to create a research agenda

leading to a larger comparative effectiveness study con-ducted by international collaborators in three countries,and the study reported here was conceived as necessarypreliminary research to an international trial of acupunc-ture point injection of vitamin K in SP6 vs NSAIDs, whichwould be executed in the three countries where pilotresearch had been successfully conducted. Studies inEurope, North America and Asia have indicated that thistreatment reduces menstrual pain in young women withprimary dysmenorrhoea, in a variety of outpatient set-tings in diverse cultures. The results of these studies as agroup indicate that various forms of vitamin K (K1, K4

and K3) can produce pain relief when utilised with acu-puncture point injection and have also indicated that thetreatment is adaptable to various clinical settings (publichealth clinics, private practice, hospital outpatient facil-ities) and acceptable to young women in North Americaand Europe, as well as in China.1417 The study reportedhereisone of two known randomised studies of the treat-ment17 and has the largest sample size and most rigorousdesign of all known studies on the treatment. Resultsreported here also suggest that both the agent and site ofinjection inuence the effect size of the short-term painreduction measures.

Study limitationsThe study setting may limit generalising the results.Expectation by Chinese women that acupuncture willprovide pain relief may have inuenced reports of painreduction. However, this limitation is mitigated by theresearch efforts of international collaborators who haveimplemented the clinical protocol in a variety of coun-tries and settings. The hypothesised optimal treatmentin this study has been tested on Chinese, American andItalian women with primary dysmenorrhoea and hasreduced menstrual pain in young women in publichealth clinics, private practice and hospitals.14 15 17 The

study was implemented in two phases under two differ-ent randomisation schemes and data from the rstphase were analysed prior to the implementation of thesecond phase of the study. Initially, the study team com-pleted a pilot study of 36 patients and analysed the data.Since the hypothesised results were positive and theeffect size was robust, the study was powered and datawere collected for another 44 patients for more stableresults. We performed analysis stratied by the twophases and found no signicant differences in results byphase, which supports our methodological approach ofanalysing and reporting the combined results. Menstrualdistress scores on two different scales were compared

Table 4 Analgesic tablet consumption at baseline and six

follow-up cycles

Group B

Group A

(Control for

vitamin K)

(Control for

point

location)

Group C

(Standard)

Mean (SD) Mean (SD) Mean (SD)

Baseline 0.93 0.82 0.82 0.56 0.89 0.77Cycle 2 0.22 0.42 0.41 0.57 0.27 0.45

Cycle 3 0.11 0.32 0.33 0.48 0.35 0.49

Cycle 4 0.22 0.42 0.41 0.5 0.27 0.45

Cycle 5 0.22 0.42 0.48 0.5 0.35 0.49

Cycle 6 0.33 0.48 0.48 0.58 0.23 0.43

Cycle 7 0.22 0.42 0.33 0.48 0.23 0.43


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with Student t tests and not in an adjusted model formultiple comparisons.

The study took over 6 years to complete in a very busyoutpatient clinic. Recruitment during the second phaseof the study became ever more challenging. Whereasthe rst phase received external funding, in the secondphase the funding was greatly reduced, limiting therelease time of the study physicians and making the

6 months of follow-up data collection difcult.Scheduling difculties also affected recruitment, as it isimportant for participants to be treated within 2 days ofonset of menses and at the height of their pain.However, this was not always possible, and this limitedparticipation in the study.

CONCLUSIONOur study reports the effect of acupuncture point injec-tion of vitamin K3 on the pain of dysmenorrhoea inyoung Chinese women. It extends the work of previoussingle-arm and cross-over studies through the implemen-

tation of a randomised parallel group design, and pro-vides substantial evidence that the treatment providespain relief for women with painful periods who have notbeen able to obtain satisfactory relief by any othermethod. Study results also indicate that the site of injec-tion and the specic agent of vitamin K, specicallyvitamin K3, are crucial to the optimal treatment of paindue to primary dysmenorrhoea.

Author affiliations1Richard & Hinda Rosenthal Center for Complementary and Alternative

Medicine Research, College of Physicians and Surgeons, Columbia University,

New York, New York, USA2

Institute of East West Medicine, New York, New York, USA3Obstetrics and Gynecology Hospital, Fudan University, Shanghai, Shanghai,

China4Agenzia Sanitaria e Sociale Regionale dellEmilia Romagna, (Healthcare and

Social Agency of Emilia Romagna Region), Viale Aldo Moro, 21, 40127

Bologna, Italy5Department of Anesthesiology, Pain and Perioperative Medicine, Stanford

University School of Medicine, Palo Alto, California, USA6Department of Statistics, Columbia University, New York, New York, USA7Department of Statistics, School of Public Health, Fudan University,

Shanghai, Shanghai, China8Osher Center for Integrative Medicine, University of California at

San Francisco, San Francisco, California, USA

Contributors CW contributed to the study design, project management, data

analysis and interpretation, and wrote the first draft of the manuscript. LW,WJZ and SQG contributed to the study design and procedures, data

acquisition and quality, study administration and interpretation of results. FC

contributed to the study design and interpretation of results. FK obtained the

study funding and participated in the administration and data acquisition. ZY

was responsible for the power calculation, statistical analysis and

interpretation and data monitoring. NQZ was responsible for the

randomisation, blinding, statistical analysis and interpretation and data

monitoring. MTC performed the statistical analysis and interpretation. JY

developed the treatment protocol and provided the pilot data.

Funding Funding was provided by an NIH/NCCAM Planning Grant for

International Research on Chinese Medicine and Womens Health

(R21-AT01957), the Obstetrics and Gynecology Hospital, Shanghai, China and

the Institute of East/West Medicine, New York, New York, USA. Additional

funding was received through NIH/NCCAM (K01AT006545).

Disclaimer The contents of this paper are solely the responsibility of the

authors and do not necessarily represent the official views of the NIH or

NCCAM or other funders.

Competing interests None declared.

Ethics approval Columbia University Medical Center IRB, New York, USA:

Obstetrics and Gynecology Hospital Medical Ethics Board, Shanghai, China.

Provenance and peer review Not commissioned; externally peer reviewed.

Data sharing statement No additional data are available.

Open Access This is an Open Access article distributed in accordance with

the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license,

which permits others to distribute, remix, adapt, build upon this work non-

commercially, and license their derivative works on different terms, provided

the original work is properly cited and the use is non-commercial. See: http://

creativecommons.org/licenses/by-nc/4.0/

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double blind, controlled studyprimary dysmenorrhoea: a randomised,Acupuncture point injection treatment of

Q Zhao, M T Chao and J YuC Wade, L Wang, W J Zhao, F Cardini, F Kronenberg, S Q Gui, Z Ying, N

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BMJ Acupuncture point injection treatment of primary dysmenorrhoea