Acupuncture versus topiramate in chronic migraine prophylaxis

Original Article

Acupuncture versus topiramate in chronicmigraine prophylaxis: A randomizedclinical trial

C-P Yang1,2, M-H Chang3, P-E Liu4, T-C Li4,5, C-L Hsieh5,K-L Hwang6 and H-H Chang2,7

Abstract

Background: The aim of this study was to investigate the efficacy and tolerability of acupuncture compared with topir-

amate treatment in chronic migraine (CM) prophylaxis. Methods: A total of 66 consecutive and prospective CM patients

were randomly divided into two treatment arms: 1) acupuncture group: acupuncture administered in 24 sessions over 12

weeks (n¼ 33); and 2) topiramate group: a 4-week titration, initiated at 25 mg/day and increased by 25 mg/day weekly to

a maximum of 100 mg/day followed by an 8-week maintenance period (n¼ 33).

Results: A significantly larger decrease in the mean monthly number of moderate/severe headache days (primary end

point) from 20.2� 1.5 days to 9.8� 2.8 days was observed in the acupuncture group compared with 19.8� 1.7 days to

12.0� 4.1 days in the topiramate group (p< .01) Significant differences favoring acupuncture were also observed for all

secondary efficacy variables. These significant differences still existed when we focused on those patients who were

overusing acute medication. Adverse events occurred in 6% of acupuncture group and 66% of topiramate group.

Conclusion: We suggest that acupuncture could be considered a treatment option for CM patients willing to undergo this

prophylactic treatment, even for those patients with medication overuse.

Keywords

Acupuncture, chronic migraine, prophylaxis, topiramate

Date received: 15 April 2011; revised: 2 June 2011; accepted: 6 July 2011

Introduction

According to the second edition of the InternationalClassification of Headache Disorders (ICHD-II) andthe subsequently revised ICHD-II criteria, chronicmigraine (CM) is characterized by headache on atleast 15 days per month, of which at least 8 headachedays per month meet the criteria for migraine withoutaura or respond to migraine-specific treatment (CM-R,A1.5.1) (1,2). It is believed that medication overusecontributes to its development and blocks attempts atprevention (3). Approximately 1.4% to 2.2% of thegeneral population suffers from CM (4–8). Patientswith CM present a clinical treatment challenge. Thispopulation is associated with significant disability, psy-chological distress, reduced health-related quality oflife, and considerable healthcare cost (9–11). Untilnow, only topiramate and local injections of botulinumtoxin have been shown to be effective in placebo-con-trolled randomized trials for CM prophylaxis (12–19).However, the high cost of botulinum toxin and consid-erable side effects of topiramate preclude their wide usefor CM.

Acupuncture is one of the most commonlyresearched and widely accepted complementary andalternative medicine therapies in the treatmentof migraine (20–23). A Cochrane systemic review con-cluded that there is no evidence for an effect of trueacupuncture over sham interventions, although thisis difficult to interpret, as the exact point location couldbe of limited importance. Available studies suggest thatacupuncture is at least as effective as, or possibly more

1Kuang Tien General Hospital, Taiwan.2Chang Gung University, Taiwan.3National Yang-Ming University, Taiwan.4Huang-Kuang University, Taiwan.5China Medical University, Taiwan.6Chung Shan Medical University, Taiwan.7Chang Gung Memorial Hospital, Taiwan.

Corresponding author:

Dr Hen-Hong Chang, Center for Traditional Chinese Medicine, Chang

Gung Memorial Hospital, 123 Dinghu Rd, Guishan Township, Taoyuan

County 33378, Taiwan

Email: [email protected]

Cephalalgia

31(15) 1510–1521

! International Headache Society 2011

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DOI: 10.1177/0333102411420585

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effective than, prophylactic drug treatment, and hasfewer adverse effects (AEs). Acupuncture should beconsidered a treatment option for patients willing toundergo this treatment (23). However, most of thesestudies were conducted in patients with episodicmigraine. There have not been any rigorous trials forthe evaluation of the efficacy and safety of acupuncturetreatment versus proven effective drugs on CM.

In an attempt to investigate the efficacy and tolera-bility of acupuncture compared with topiramate treat-ment in patients with CM, we conducted a prospective,randomized clinical study under conditions similar toroutine care. In addition, we evaluated the subgroup ofpatients with medication overuse in both treatmentgroups.

Methods

Study design

The present study was developed at the Department ofNeurology of Kuang-Tien General Hospital. The pro-tocol and supporting documents (information sheet,consent form, and protocol) were approved by the insti-tutional ethics committee in June 2008. The recruitmentof patients was done from August 2008 to October2010, and the trial was completed in January 2011.Patients were recruited via the outpatient department.They were scheduled by the research assistants andevaluated by an experienced neurologist. This studyconsisted of two periods: prospective baseline periodbefore enrolment (week -4 to week 0) and treatmentperiod (week 0 to week 12) after enrolment.

Inclusion and exclusion criteria were checked againstdata from the baseline period. The inclusion criteriawere: an age of 18–65 years; a diagnosis based on thepublished guidelines of the Task Force of theInternational Headache Society Clinical TrialsSubcommittee for controlled trials of prophylactictreatment of CM in adults criteria A–C (referring tothe clinical characteristics of headache) but not crite-rion D of CM-R (the criteria for medication overuseheadache, MOH-R, can also be met) during the 3months before trial entry; and an established migrainehistory for at least 1 year (24). Participants with MOH-R must be stratified accordingly (25).

Patients were excluded if any of the following werepresent: 1) the headache was experienced for �15 daysper month or there was no response to triptans orergots on at least 8 days during the prospective baselineperiod (a 4-week preliminary phase); 2) headachesother than CM (such as another primary chronic head-ache or any secondary headache except medicationoveruse headache (25)); 3) migraine prophylaxisagents had been used in the past 3 months, such as b-

blockers, anti-depressants, calcium channel blockers,anti-epileptic agents, cycle-modulating hormonaldrugs, or vessel dilatation agents; 4) migraine onsetafter the age of 50, or over 60 years of age at onset ofCM; 5) history of hepatic disorder, nephrolithiasis orother severe illness; 6) cognitive impairment interferingwith the participant’s ability to follow instructions anddescribe symptoms; 7) previous fearful experience ofacupuncture or receiving acupuncture in the past 3months; 8) bleeding diathesis or using anticoagulationagents; 9) pregnancy or nursing; or 10) severe depres-sion (Beck Depression Inventory-II (BDI-II) score �30at baseline day 1). If the patients fulfilled the criteriaand gave written informed consent, they were enrolledin the study.

After enrolment, the patients were randomized intotwo treatment arms: 1) acupuncture group: acupunc-ture administered in 24 sessions over 12 weeks; and 2)topiramate group: a 4-week titration, initiated at 25mg/day and increased by 25mg/day weekly to a maximumof 100mg/day (or to the maximal tolerated dose) fol-lowed by an 8-week maintenance period. At the end ofthe baseline screening phase, randomization was doneprovided the participants met the quantitative inclusionand exclusion criteria as per their reported diary data.The randomization was done according to computer-generated randomly allocated treatment codes, anddata were kept by a person not involved in the careor evaluation of the patients or in the data analysis.Patients were allowed to take acute headache medica-tion prescribed by our neurologists. We required thatthe acute headache medication be the same throughoutthe baseline period and for the duration of treatmentperiod, and this was documented daily throughout thecourse of the study. All patients were scheduled so as toavoid any overlap during which they could share clin-ical information and experiences with each other.

Clinical assessments

All participants began the study by completing a set ofoutcome measures: the Migraine Disability Assessment(MIDAS), Short-Form 36 (SF-36), BDI-II andHospital Anxiety and Depression Scale (HADS). Allfour questionnaires were administered on day 1 of thebaseline period and repeated at the end of the treatmentphase. To ensure consistency, the evaluating physicianwas the same person on each occasion for each patient,and was blinded to the type of treatment. Patients hadto keep a headache diary from the baseline period(diary 1) and treatment period (diaries 2–4). Eachdiary covered 4 weeks. Daily calendar entries weredesigned to assess the frequency, location, duration,peak severity (1, mild; 2, moderate; 3, severe headachepain), presence of aura, menstruation, concomitant

Yang et al. 1511

symptoms, the number of days with acute headachemedication intake (including amount and frequencyof analgesic drugs) for each migraine attack andstudy medication received.

Treatments

Acupuncture treatment

Acupuncture consisted of 24 sessions of 30min, admin-istered over 12 weeks (two sessions per week). Eachpatient had fixed and classic acupuncture points, bilat-eral Cuanzhu (BL-2), Fengchi (GB-20), Taiyang (EX-HN-5) and midline Yintang (Ex-HN-3) (Figure 1) intheir 24 sessions without modification for the specificsymptoms of the patient. All of the selected acupointswere in the distribution of trigeminal and cervical der-matomes related to the trigeminal sensory pathway. Weplaced patients in the sitting position and acupunctureneedles were tapped into place through sterile plasticguide tubes. At each point, the needle was manipulatedby twirling with lifting-thrusting slowly until the partic-ipant felt De Qi (an awareness of warmth, numbness,soreness, swelling, heaviness or radiation deemed toindicate proper needle position and effective needling).Seven sterile disposable steel needles (gauge and size:0.25mm� 40mm) were used without electrical stimula-tion or moxibustion (burning of mugwort). They werethen left in place for 30min. Participants were free to

discontinue the treatment any time, for any reason. Alltreatments were performed by one acupuncturist at thesame facility, and the acupuncturist was asked to havethe least possible communication with the patients tominimize bias. Complete details of the intervention arepresented in Table 1 in conformance to the standardsfor reporting interventions in controlled trials of acu-puncture (STRICTA) (26).

Topiramate treatment

Patients assigned to the topiramate group also under-went treatment for 12 consecutive weeks. The treatmentphase consisted of a 4-week titration period and an 8-week maintenance period. During the titration period,participants were given topiramate 25mg/day at bedtimefor 1 week, followed by weekly increases of 25mg up toeither 100mg/day of topiramate or to the maximal toler-ated dose. Starting in week 2, topiramate was given dailyin equally divided twice daily doses. During the mainte-nance period, a stable topiramate dose of at least 50mg/day was required. All participants were required tofollow the same titration schedule. The mean final topir-amate maintenance dose was 84.0mg/day.

Primary efficacy parameters

The monthly number of moderate/severe headachedays (a day with headache pain that lasted� 4 hours

Ex–HN–5 (V2)

Ex–HN–3 (V1)

GB–20 (C2)

BL–2 (V1)

Figure 1. Location of the acupoints used (all bilateral except Ex-HN-3, which is located at the head midline) and their relation to the

dermatomes. Dermatomes are listed with the following abbreviations: V1, ophthalmic branch of the trigeminal nerve; V2, maxillary

branch of the trigeminal nerve; C2, dermatome of the second cervical nerve.

1512 Cephalalgia 31(15)

with a peak severity of moderate or severe intensity, orany severity or duration if the participant took andresponded to a triptan or ergot) from the second tothe fourth diaries compared with the first diary (base-line period).

Secondary efficacy parameters

There were eight secondary efficacy parameters, as fol-lows: 1) monthly number of headache days (any inten-sity) from the second to the fourth diaries comparedwith the first diary (baseline period); 2) change ofMIDAS scores from baseline to endpoint; 3) changeof HADS scores from baseline to endpoint; 4) changeof SF-36 scores from baseline to endpoint; 5) change ofBDI-II scores from baseline to endpoint; 6) reductionfrom baseline in the number of days with acute head-ache medications, from the second to the fourth diariescompared with the first diary (baseline period); 7)�50% reduction in monthly moderate/severe headachedays from the second to the fourth diaries comparedwith the first diary (baseline period); 8) �50% reduc-tion in monthly headache days from the second to thefourth diaries compared with the first diary (baselineperiod).

Safety assessments

Medical and headache histories were recorded, physicaland neurological examinations were performed, andclinical laboratory parameters (hematology and chem-istry evaluations) were assessed at screening and thefinal visit (week 12). Women of childbearing potentialhad urine pregnancy tests. After enrolment, partici-pants in the topiramate group were required to returnfor a doctor visit once a week during the first month of

the titration period, and then return to monitor anyAEs of the drug at the end of a month during the fol-lowing 2 months of treatment period (six visits in total).Participants in the acupuncture group were seen twice aweek for acupuncture treatment and to monitor AEs ineach session for the whole three months (24 visits intotal). We recorded AEs such as nausea, dizziness, par-esthesia, fatigue, dyspepsia, somnolence, and nauseaalong with ecchymosis, local paresthesia or bleedingfor all enrolled patients.

Statistical analysis

Data analysis was performed separately for all studyparticipants and for a subgroup of participants whowere overusing acute headache medication.Medication overuse was defined as intake of simpleanalgesics (e.g. aspirin, acetaminophen, or non-steroidanti-inflammation drugs) on more than 15 days permonth or the intake of a combination of analgesics,opioids, ergots, or triptans on more than 10 days permonth (25). A last-observation-carried-forwardapproach was used to impute missing data with theintent-to-treat analysis principle. All outcome variableswere examined with the assumption of normality usingthe Kolmogorov-Smirnov test, and the assumption washeld for all outcome variables. Thus, independent two-sample t-tests were performed to compare the changesin mean monthly number of moderate/severe headachedays and other efficacy assessments between the twogroups. Paired t-tests were performed for changes inall efficacy evaluations between month 3 data and base-line data within each treatment group. The proportionsof participants with �50% reduction of moderate/severe headache days and participants with �50%reduction of headache days were compared between

Table 1. Standards for reporting interventions in controlled trials of acupuncture (STRICTA)

Acupuncture rationale and needling details

Fixed and classic acupuncture points Bilateral Cuanzhu (BL-2), Fengchi (GB-20), Taiyang (EX-HN-5) and midline

Yintang (Ex-HN-3) in the 24 sessions

Depth of insertion Standard to each point according to classic acupuncture point

Responses elicited De Qi sensation

Manual Twirling with lifting-thrusting method stimulation

Time needles retained 30 min

Needle type Carbo and Viva; 32 (Chinese) gauge, 25–40 mm (body points); gauge and size:

0.25� 40 mm

Treatment regimen Twice per week for 12 weeks

Co-interventions None: no herbs, moxibustion, cupping, rehabilitation, advice regarding dietary

or lifestyle modifications

Practitioner background License-certificated

Control interventions Nil

Yang et al. 1513

the two groups with the chi-square test or Fisher’s exacttest when appropriate. All hypothesis testing was two-tailed and the level of significance was set at 0.05. Allstatistical analyses were performed using SPSS Version15.0 for Windows (SPSS Inc., Chicago, IL, USA)

Results

Enrolment of patients and baseline characteristics

A total of 66 patients who were eligible and agreed toparticipate in our study were randomly allocated toeither the acupuncture or topiramate treatment group.Of the 66 patients, one patient in the acupuncturegroup dropped out owing to an inability to take timeoff work, and three patients in the topiramate group didnot finish the study owing to intolerance of side effects.The dropout rate was low for both topiramate and acu-puncture groups. We imputed baseline values for themissing data of the four patients who did not completethe study (setting the differences from baseline to zero).

Figure 2 illustrates patient enrolment and random allo-cation of the patients to the study groups. The baselinecharacteristics of the two groups were similar in theintention-to-treat population (Table 2). Most patientsmet the medication overuse headache criteria at base-line (Table 2). The subgroup of patients who were over-using acute headache medication (n¼ 49, 74.2%)consisted of 24 patients receiving acupuncture and 25receiving topiramate treatment. There were also no sig-nificant differences in demographics and baseline char-acteristics between the acupuncture-treated andtopiramate treated patients for this subgroup (Table 2).

Outcome of treatment

Primary efficacy parameters: numbers of moder-ate/severe headache days

There was a substantial mean reduction from baselinein the number of headache days in both treatmentgroups (Table 3). However, acupuncture was

Failure to meet

criteria during the

baseline period

(n =8); Refused to

participate (n =14)

Discontinued

intervention due to

inability to take time

off work (n =1)

Completed intervention

(n =32)

Allocated to the

acupuncture group

(n =33)Allocation

Completed 3

months study

Discontinued

intervention due to

side effects (n =3)

Completed

intervention (n =30)

Allocated to the

topiramate group

(n =33)

Patients screened (n =88)

Enrollment

Randomization

Intention-to-treat analysis

(Data for 1 patient in the acupuncture

group and 3 patients in the topiramate

group were imputed by

last-observation-carried-forward

approach for intention-to-treat)

Figure 2. Flow chart of process and disposition of patients.

1514 Cephalalgia 31(15)

statistically significantly more effective than topiramatein reducing the mean monthly number of moderate/severe headache days (�10.5� 2.8 acupuncture vs�7.8� 3.6 topiramate; p< .01) (Table 3). The samepattern was also observed among the subgroup ofpatients who were overusing acute headache medica-tion (�10.4� 2.9 acupuncture vs �8.1� 3.6 topiramatefor the mean change of monthly number of moderate/severe headache days; p¼ .016) (Table 3).

Acute headache medications taken

There was a significant reduction in the number of dayswith acute headache medication intake in both groups,and a significantly greater reduction was observed inthe acupuncture group compared with the topiramategroup among all participants (�9.6� 3.3 acupuncturevs �5.4� 4.7 topiramate; p< 0.01) and in the partici-pants who were overusing acute headache medication(�8.7� 3.1 acupuncture vs �5.9� 4.6 topiramate;p¼ .014) (Table 3).

50% responder analyses

A significantly greater percentage of the participants inacupuncture group than in topiramate group had atleast a 50% decrease from baseline in the number ofmoderate/severe headache days (acupuncture 75.8%and 79.2% vs topiramate 30.3% and 32.0% for all par-ticipants and the medication overuse subgroup, respec-tively; all p< .01). In addition, a greater percentage ofthe participants in acupuncture group than in topira-mate group had at least a 50% decrease from baselinein the number of headache days (acupuncture 63.6%and 70.8% vs topiramate 15.2% and 20.0% for all par-ticipants and the medication overuse subgroup, respec-tively; all p< .01) (Figure 3).

Headache impact on disability, psychological dis-tress and health-related quality of life

Statistically significant and clinically meaningful differ-ences for acupuncture versus topiramate were observed

Table 2. Baseline demographics and characteristics of the two groups

All participants Participants with medication overuse

Acupuncture Topiramate Acupuncture Topiramate

N 33 33 24 25

Age (years) 47.6 (7.4) 48.1 (6.4) 48.3 (6.3) 48.3 (7.1)

Sex (male/female) 3/30 4/29 1/23 3/22

Duration of CM (years) 13.2 (3.5) 13.5 (4.5) 13.0 (4.0) 13.2 (5.0)

Percentage of patients who overused acute

headache medications at baseline

72.70% 75.70%

Mean headache days per month 21.3 (1.6) 21.0 (1.4) 21.6 (1.6) 21.1 (1.4)

Mean moderate/severe headache days per

month

20.2 (1.5) 19.8 (1.7) 20.5 (1.5) 19.9 (1.6)

Mean MIDAS score 60.7 (6.7) 60.1 (5.1) 60.9 (7.2) 60.4 (5.3)

Mean BDI score 16.4 (3.3) 16.8 (2.7) 16.7 (3.1) 16.8 (2.6)

Mean HADS score 11.5 (1.8) 11.7 (1.6) 11.6 (2.0) 11.8 (1.3)

Mean number of days with acute headache

medication intake per month

15.1 (2.3) 14.5 (2.6) 14.7 (2.2) 15.0 (2.7)

Mean domain of SF-36

Physical function (PF) 64.3 (9.7) 64.6 (9.1) 64.8 (9.9) 66.0 (8.7)

Role physical (RP) 50.1 (8.8) 49.8 (7.9) 49.3 (6.2) 50.3 (8.3)

Bodily pain (BP) 51.8 (4.7) 52.4 (7.8) 52.0 (4.2) 52.5 (7.2)

General health (GH) 48.8 (7.9) 46.6 (6.6) 49.6 (8.1) 47.6 (7.2)

Vitality (VT) 37.7 (6.0) 36.6 (6.4) 37.1 (5.9) 36.4 (5.9)

Social functioning (SF) 61.7 (7.4) 63.1 (6.0) 60.9 (7.4) 64.4 (5.0)

Role emotion (RE) 48.9 (11.3) 49.4 (10.6) 50.4 (12.0) 50.6 (11.6)

Mental health (MH) 55.5 (7.3) 55.7 (8.0) 55.1 (7.4) 56.1 (7.4)

Values are n, mean (SD), or percent.

MIDAS, Migraine Disability Assessment; BDI-II, Beck Depression Inventory-II; SF-36, Short-Form 36; HADS, Hospital Anxiety and Depression Scale;

SD, standard deviation.

Yang et al. 1515

Table 3. Mean changes from baseline of the two groups

All participants Participants with medication overuse

Acupuncture Topiramate Acupuncture Topiramate

Mean change SD Mean change SD SIG Mean change SD Mean change SD SIG

Mean headache days per

month

�10.7 2.8 �7.9 3.6 ** p< .01 �10.6 3.0 �8.3 3.8 ** p¼ .022

Mean moderate/severe

headache days per

month

�10.5 2.8 �7.8 3.6 ** p< .01 �10.4 2.9 �8.1 3.6 ** p¼ .016

Mean MIDAS score �38.5 10.7 �25.9 9.3 ** p< .01 �38.5 12.1 �26.8 8.8 ** p< .01

Mean BDI-II score �7.7 4.8 �5.6 2.4 ** p¼ .025 �8 4.5 �5.6 2.4 ** p¼ .029

Mean HADS score �7.1 2.2 �2.9 1.7 ** p< .01 �7.1 2.2 �3.2 1.6 ** p< .01

Mean number of days with

acute headache medi-

cation intake per month

�9.6 3.3 �5.4 4.7 * p< .01 �8.7 3.1 �5.9 4.6 ** p¼ .014

Mean domain of SF-36

Physical function (PF) 18.7 9.2 9.2 4.9 ** p< .01 18.2 9.7 9.3 4.5 ** p< .01

Role physical (RP) 27.6 8.9 18.2 9.3 ** p< .01 27 7.4 18.5 10.0 ** p¼ .02

Bodily pain (BP) 13.7 8 8.1 4 ** p¼ .01 12.6 7.4 8 4.0 ** p¼ .011

General health (GH) 22.3 6.9 14.8 11.9 ** p¼ .002 21.9 6.8 13.6 12.6 ** p¼ .007

Vitality (VT) 22.1 6.6 16.8 6.6 ** p¼ .002 21.4 6.9 17.2 6.5 ** p¼ .032

Social functioning (SF) 16 8.1 9.8 4.7 ** p< .01 16.3 9 10.3 4.6 ** p¼ .007

Role emotion (RE) 27.8 10.7 17.5 6.2 ** p< .01 26.6 11 17.6 5.9 ** p¼ .001

Mental health (MH) 22.2 6.4 11 6.5 ** p< .01 21.9 7.3 11.8 6.8 ** p< .01

MIDAS, Migraine Disability Assessment; BDI-II, Beck Depression Inventory-II; SF-36, Short-Form 36; HADS, Hospital Anxiety and Depression Scale;

SD, standard deviation; SIG, significance. p-value by independent t-test to compare the mean changes from baseline between groups. *: p< .05; **:

p< .01 by paired t-test for significant changes from baseline within group.

63.6

75.870.8

79.2

15.2

30.320

32

Headache Moderate/severe headache Headache Moderate/severe headache0

20

40

60

80

100

% o

f sub

ject

s w

ith r

educ

tion

in d

ays

≥50

%

Acupuncture Topiramate

**** **

** P < .01

**

All subjects Medication Overuse

Figure 3. Percentages of participants having at least a 50% decrease from baseline in the number of moderate/severe headache days.

A significantly greater percentage of the acupuncture group than topiramate group had at least a 50% decrease from baseline in both

measures by Fisher’s exact test for all participants and the subgroup of patients who were overusing acute medication (all p< .01).

1516 Cephalalgia 31(15)

in the mean change from baseline to endpoint inMIDAS score for all participants and the subgroup ofpatients who were overusing acute headache medica-tion (p< .01) (Table 3). Acupuncture treatmentshowed a significantly greater improvement when com-pared to topiramate treatment in HADS (p< .01),BDI-II (p¼ .025) and overall health-related quality oflife (SF36) (p< .05), as measured by changes from base-line for all participants (Table 3). The same pattern wasalso observed for the subgroup who were overusingacute headache medication (p< .01 for MIDAS andHADS, p¼ .029 for BDI-II and p< .05 for overallhealth-related quality of life (SF36) (Table 3). All effi-cacy evaluations showed significant improvement frombaseline for each group (all p< .05), and the acupunc-ture group demonstrated a significantly better improve-ment for all of the assessments when compared with thetopiramate group among all participants as well as forthe subgroup of patients who were overusing acuteheadache medication (all p< .05).

Adverse side effects

No serious AEs or deaths were noted. In the acupunc-ture group, side effects were reported by 6% of thepatients. Most AEs were related to the local insertionof the needles, such as local pain after the session,ecchymosis, and local paresthesia during the session.Acupuncture was well tolerated by the patients, andno one discontinued prematurely because of needle-related side effects. One patient in the acupuncturegroup discontinued treatment because of inability totake time off work. In the topiramate group, AEswere reported by 66% of the patients. The most fre-quently noted adverse effects were paresthesia (n¼ 16,48.4%), difficulty with memory (n¼ 12, 36.3%), dys-pepsia (n¼ 12, 36.3%), fatigue (n¼ 8, 24.2%), dizziness(n¼ 7, 21.2%), somnolence (n¼ 6, 18.1%), and nausea(n¼ 5, 12.1%). Most of the AEs were mild and self-limiting, but three (9%) of the patients withdrew fromtreatment because of intolerable adverse effects.

Discussion

The present study is one of the most rigorous trials ofthe efficacy of acupuncture treatment versus proveneffective available drugs on CM. The strengths of ourprospective study include interventions, assessments,and outcome measurements as recommended in theguidelines for trials on CM (24). A clearly describedprocedure for acupuncture treatment following theSTRICTA (standards for reporting interventions incontrolled trials of acupuncture) guidelines makes our

study reproducible (26), and our study demonstratedthe efficacy in the prophylactic treatment of CM inboth acupuncture and topiramate groups.Acupuncture, when compared with topiramate,proved to be more effective in reducing the monthlynumber of moderate/severe headache days, monthlynumber of headache days, headache disability, psycho-logical distress, and overall health-related quality of lifeat month 3 from the baseline. In addition to the resultsof the primary efficacy endpoint, a significantly greaterpercentage of acupuncture-treated than topiramatetreated patients had at least a 50% decrease from base-line in the number of headache days and number ofmoderate/severe headache days. Acupuncture versustopiramate treatment also resulted in highly significantimprovements from baseline in disability, psychologicaldistress, and overall health-related quality of life. Thesefindings indicate that the benefits of the acupuncturetreatment were clinically meaningful to the patients. Itcan thus be concluded that acupuncture treatment has asuperior efficacy and less side effects when comparedwith topiramate treatment for patients with CM.

Safety is an important consideration in the manage-ment of chronic conditions such as CM, and fewertreatment-related AEs were reported among patientswho received acupuncture (6%) than among those trea-ted with topiramate (66%). Three (9%) of the topira-mate patients discontinued the study owing to AEs. Incontrast, no patients in the acupuncture group discon-tinued the study owing to AEs, a result that is consis-tent with the known safety and tolerability profiles ofacupuncture (27–30). The low drop-out rates may bedue to three factors: 1) Our hospital is the largest in theregion and is ranked as the highest in terms of quality.We build good relationships with our patients, resultingin low drop-out rates. 2) In topiramate group, AEswere reported by 66% of the patients; however, mostof the AEs were mild and self-limiting so most did notlead to further drop-outs. In acupuncture group, minorside effects were reported by 6% of the patients andnone discontinued prematurely because of needle-related side effects. 3) The treatment sessions were rel-atively short.

With CM being a disabling and rather difficult con-dition to treat, alternative therapeutic options such asacupuncture should be explored. A recent Cochranesystemic review concluded that acupuncture is at leastas effective as, or possibly more effective than, prophy-lactic drug treatment, and has fewer adverse effects.However, there is no evidence for an effect of true acu-puncture over sham interventions. Acupuncture shouldbe considered a treatment option for patients willing toundergo this treatment (23). Indeed, sham acupuncturemay still induce a wide range of peripheral, segmentaland central physiological responses to an unpredictable

Yang et al. 1517

degree (31–35). The possible reasons that previous trialscould not detect the difference between true and shamacupuncture was that they assume there was no treat-ment effect for sham acupuncture in estimating theeffect size. True acupuncture is widely used in Asiaand topiramate treatment is the usual therapy forCM. Our findings of the treatment effects of true acu-puncture versus topiramate provide useful informationin clinical practice.

Currently, the US Food and Drug Administrationhas approved onabotulinumtoxinA, based onPREEMPT (Phase III REsearch Evaluating MigraineProphylaxis Therapy with Botulinum Toxin Type A)trials for the prophylactic treatment of headaches inadults with CM (17–19). However, the high cost pre-cludes its routine use for CM. Other preventive treat-ments, such as propranolol, valproic acid, flunarizineand topiramate for episodic migraines, are widely usedfor CM management, but none of these drugs has beenapproved for CM prophylaxis (36–38). Topiramate, arelatively new anticonvulsant, has been shown to beeffective in placebo-controlled randomized trials forCM (13,14,16). We compared our results with thoseof the other two CM preventive studies; one is the larg-est trial for topiramate prevention for CM and theother is pooled data of PREEMPT studies (13,19).The mean number of headache days decreased by10.7 days per 4 weeks for acupuncture group and by7.9 days per 4 weeks for topiramate group in our study,and this difference was significant. The 7.9 daysdecrease in the mean number of headache days fortopiramate group in our study is comparable to thatfor topiramate group reported by Silberstein et al.(13) (6.4 days per 4 weeks), and to that for botulinumtoxin group reported by the pooled data of PREMMPTstudies (19) (8.4 days per 4 weeks). In our study, themean dosage of topiramate was 84.0mg/day, which isconsistent with previous studies where low dose topir-amate (<100mg per day) was shown to be an effectiveprophylaxis agent for CM (13,14,16). In compari-son with the other acupuncture studies to date(39,40), there is no rigorous trial for the evaluationof the efficacy of acupuncture treatment versusproven effective drugs on CM. However, we had a sim-ilar conclusion in that acupuncture is similarlyeffective or more effective than prophylacticdrug treatment with less side effects in migraineprophylaxis.

This trial has another important finding. It is wellknown that for preventive agents to be successful, med-ication overuse must first be controlled (detoxification)(3). It is widespread practice to withdraw patients frommedication overuse on an out-patient or in-patientbasis with adjunctive treatment. This was clearly notdone in the present study because we observed an

estimated reduction in the number of monthly moder-ate/severe headache days and number of headache daysfor the acupuncture group for all participants and forparticipants who were overusing acute headache medi-cation during the 28-day baseline period. Similar effectswere observed for the topiramate group. This indicatesthat overusing medication did not have an impact ontreatment effect, and that withdrawing patients withCM from medication overuse may not be necessaryprior to the initiation of acupuncture or topiramatetreatment. These findings agree with previously pub-lished data observed on topiramate for CM andPREMMPT studies (12,16–19). From another pointof view, the improvement across multiple efficacy end-points among the acupuncture-treated patients com-pared with topiramate-treated patients, with anaccompanying significant difference in the meannumber of days on which acute headache medicationwas taken, may be that acupuncture made it easier forthe patients to withdraw the acute headache medicationand that the improvement resulted from detoxificationand not from the acupuncture itself.

Traditional acupuncture has its own diagnosticsystem for headaches, in that treatment should be indi-vidualized (acupoints vary from person to person orfrom treatment to treatment). However, the absenceof standardized approaches to acupuncture treatmentsobstructs data reproducibility across the discipline.With this in mind, we used fixed and classic acupunc-ture points (standardized acupuncture) in all patientsduring every therapeutic session. This makes ourstudy reproducible and as scientifically rigorous as pos-sible. However, this procedure could have limited thereal effect of individualized acupuncture. Further stud-ies are needed to confirm whether real differences canbe appreciated between individualized and standard-ized acupuncture.

Some might ask how we chose the acupoints andhow they work for CM. It is assumed that a variablecombination of peripheral effects, spinal and suprasp-inal mechanisms, and cortical, psychological or ’pla-cebo’ mechanisms contribute to the clinical effects ofacupuncture (41). Current theories suggest thatmigraine is a neurovascular disorder involving corticalspreading depression, neurogenic inflammation, andvasodilation (42). Sensitization and facilitation of paintransmission in central trigeminal sensory pathwaysmay have a particularly important role in the develop-ment of CM (43). A recent study suggests that acupunc-ture may have anti-inflammatory action via release ofneuropeptides from nerve endings, including calcitoningene-related peptide (CGRP), an important mediatorof neurogenic inflammation and a potent vasodilatorduring migraine attack (41,44). We selected acupointsin the distribution of the trigeminal and cervical

1518 Cephalalgia 31(15)

dermatomes because we postulated that an interactionbetween trigeminal and cervical nociceptive inputs tothe trigeminocervical complex via acupuncture mayinhibit trigeminal-vascular activation and thus mayinhibit migraine attack. It would be of great interestto explore the effects of these acupoints on the trigem-inal-sensory pathway to provide insight into the mech-anism of these acupoints, although it is beyond thescope of this article. It is also important to understandwhat roles the peripheral as well as the central mecha-nisms have in CM patients after acupuncture treatmentin future studies.

There were several limitations to our study thatdeserve consideration. The most relevant is the use ofan active comparator without sham controls, whichcannot rule out the possibility of a placebo effect. Ahigh placebo response has been observed in migraineprophylaxis studies, which may also contribute to thebetween-group difference observed in our study (45).Parenteral procedures such as acupuncture treatmentconsistently report higher placebo response rates thanthose seen in trials using oral medication (46,47). Theplacebo response by placebo injection in thePREEMPT trials was very high, and this mode of inter-vention is very similar to acupuncture. We were awareof and capable of using sham acupuncture, but wedecided not to because the validity of sham acupunc-ture and the best way of inducing its placebo effect arestill open questions (31,48,49). In addition, the aim ofthis study was to evaluate the effectiveness of acupunc-ture in comparison with the optimal treatment for CMin current clinical practice. Furthermore, if both treat-ments are possibly effective, it is easier to encouragepatients to join the study and there are fewer ethicalproblems in adopting an active treatment arm forpatients who are looking for a treatment for their dis-comfort. Therefore, an active group instead of shamcontrol was used in this study, and topiramate, one ofthe most effective drugs in CM prophylaxis, was chosenas a comparison. Another limitation is that acupunc-ture group had more study visits (24 visits in total)compared with the topiramate group (6 visits intotal). In addition, longer contact time with a closeinteraction between patient and acupuncturist certainlyalso contributed to the observed effect. Although theresearchers were advised not to make additional con-tact with the study participants if possible, a greaterplacebo effect could have occurred in acupuncturegroup, in which patients unavoidably received moreattention and hands-on treatment. Other limitationsof our study are the study design, having a smallnumber of patients, the mono-centric study, and theunblinded study combined with the use of subjectiveoutcomes only. Consequently, the present findingsmust be interpreted with caution.

Conclusions

Despite the limitations, this randomized, controlledstudy indicates that acupuncture treatment is superiorto topiramate treatment for patients with CM acrossmultiple clinically relevant variables, including numberof moderate/severe headache days per month, headachedays per month, headache disability, and severalpatient-reported quality of life measures as well as psy-chological distress. These significant differences stillexisted when we focused on those patients who wereoverusing acute headache medication. Acupunctureshould be considered as a treatment option for CMpatients willing to undergo this prophylactic treatment,even for those patients with medication overuse. Futureclinical trials should focus on the long-term effects ofacupuncture on CM.

Acknowledgements

This study was registered with the National Institutes ofHealth, ClinicalTrials.gov identifier NCT01096420.

Funding

This work was supported by a grant from Hung KuangUniversity and Kuang Tien General Hospital.

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