Acupuncture in patients with tension-type headache: randomised control
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《英国医生杂志》
1 Centre for Complementary Medicine Research, Department of Internal Medicine II, Technische Universit?t München, Kaiserstr 9, 80801 Munich, Germany, 2 Institute of Medical Statistics and Epidemiology, Technische Universit?t München, 3 Department of Neurology, Technische Universit?t München, 4 Institute of Social Medicine, Epidemiology, and Health Economics, Charité University Medical Centre, Berlin, Germany, 5 Private practice, Munich, 6 Department of Anesthesiology, University of Munich, Munich, 7 Division of Complementary Medicine, Department of Internal Medicine, University Hospital Zurich, Switzerland
Correspondence to: K Linde Klaus.Linde@lrz.tu-muenchen.de
Objective To investigate the effectiveness of acupuncture compared with minimal acupuncture and with no acupuncture in patients with tension-type headache.
Design Three armed randomised controlled multicentre trial.
Setting 28 outpatient centres in Germany.
Participants 270 patients (74% women, mean age 43 (SD 13) years) with episodic or chronic tension-type headache.
Interventions Acupuncture, minimal acupuncture (superficial needling at non-acupuncture points), or waiting list control. Acupuncture and minimal acupuncture were administered by specialised physicians and consisted of 12 sessions per patient over eight weeks.
Main outcome measure Difference in numbers of days with headache between the four weeks before randomisation and weeks 9-12 after randomisation, as recorded by participants in headache diaries.
Results The number of days with headache decreased by 7.2 (SD 6.5) days in the acupuncture group compared with 6.6 (SD 6.0) days in the minimal acupuncture group and 1.5 (SD 3.7) days in the waiting list group (difference: acupuncture v minimal acupuncture, 0.6 days, 95% confidence interval -1.5 to 2.6 days, P = 0.58; acupuncture v waiting list, 5.7 days, 3.9 to 7.5 days, P < 0.001). The proportion of responders (at least 50% reduction in days with headache) was 46% in the acupuncture group, 35% in the minimal acupuncture group, and 4% in the waiting list group.
Conclusions The acupuncture intervention investigated in this trial was more effective than no treatment but not significantly more effective than minimal acupuncture for the treatment of tension-type headache.
Trial registration number ISRCTN9737659.
Tension-type headache is essentially defined as bilateral headache of a pressing or tightening quality without a known medical cause.1 Tension-type headache is classified as episodic if it occurs on less than 15 days a month and as chronic if it occurs more often.1 A survey from the United States found a one year prevalence of 38% for episodic tension-type headache and 2% for chronic tension-type headache.2 Acupuncture is widely used for the treatment of tension-type headache, but its effectiveness is controversial.3 In the acupuncture randomised trial in tensiontype headache (ART-TTH), we investigated whether acupuncture reduced the frequency of headache more effectively than did minimal acupuncture (superficial needling at non-acupuncture points) or no acupuncture in patients with tension-type headache.
Methods
Protocol, design, and randomisation
ART-TTH was a randomised multicentre trial comparing acupuncture, minimal acupuncture, and a no acupuncture waiting list condition. Minimal acupuncture served as a sham intervention; we included the additional no acupuncture waiting list control because minimal acupuncture is not a physiologically inert placebo. Patients were blinded to treatment in the acupuncture and minimal acupuncture arms of the study. Two blinded evaluators analysed headache diaries. The methods of the trial have been described in detail elsewhere.4
After a baseline phase of four weeks, we used a centralised telephone randomisation procedure (random list generated with sample size 2.0 by the statistician) to randomise patients, stratified by centre (block size 12 unknown to trial physicians), in a 2:1:1 ratio (acupuncture:minimal acupuncture:waiting list). We used the 2:1:1 ratio to facilitate recruitment and increase the compliance of trial physicians. All study participants provided written, informed consent, and the study conformed to common guidelines for clinical trials (Declaration of Helsinki, ICH-GCP, including certification by external audit).
Participants
Inclusion criteria were a diagnosis of episodic or chronic tension-type headache according to the criteria of the International Headache Society,1 at least eight days with headache a month in the previous three months and in the baseline period, age 18-65 years, duration of symptoms at least 12 months, completed baseline headache diary, and written informed consent. Main exclusion criteria were additional migraine headache, secondary headaches, start of headaches after age 50, use of analgesics on more than 10 days a month, prophylactic headache treatment with drugs during the previous four weeks, and any acupuncture treatment during the previous 12 months or at any time if done by the participating trial physician. Most participants were recruited through reports in local newspapers; a minority were patients who spontaneously contacted trial centres.
Interventions
We developed the study interventions in a consensus process with German acupuncture experts and societies.4 Physicians trained (at least 140 hours, median 500 hours) and experienced (median 10 years) in acupuncture delivered the interventions. Both the acupuncture and minimal acupuncture treatments consisted of 12 sessions of 30 minutes, given over eight weeks (preferably two sessions in each of the first four weeks, followed by one session a week in the remaining four weeks).
Acupuncture treatment was semistandardised. All patients were treated at "basic" points bilaterally unless explicit reasons for not doing so were given; additional points could be chosen individually (box 1). We instructed physicians to achieve "de qi" (an irradiating feeling considered to be indicative of effective needling) if possible and to stimulate needles manually at least once during each session. The total number of needles was limited to 25 per session.
The number, length, and frequency of the sessions in the minimal acupuncture group were the same as for the acupuncture group. In each session, physicians needled at least five out of 10 predefined distant non-acupuncture points (box 2) bilaterally (at least 10 needles) and superficially using fine needles. Physicians avoided "de qi" and manual stimulation of the needles.
Patients in the waiting list control group did not receive any prophylactic treatment for their headaches for a period of 12 weeks after randomisation. After that time, they received 12 sessions of the acupuncture treatment described above.
All patients were allowed to treat acute headaches as needed. Treatment was supposed to follow current guidelines5 and had to be documented in the headache diary.
Patients were informed with respect to acupuncture and minimal acupuncture as follows: "In this study, different types of acupuncture will be compared. One type is similar to the acupuncture treatment used in China. The other type does not follow the principles of traditional Chinese medicine, but has also been associated with positive outcomes in clinical studies."
Box 1: Acupuncture points used in the trial
All physicians used sterile, disposable, single use needles but were free in their choice of length and diameter of needle
Basic points
Gall bladder (GB) 20
GB 21
Liver (LIV) 3
Optional points
Mainly frontal headache: large intestine (LI) 4, Du Mai (DU) 23, extra points Yintang and Taiyang, stomach (ST) 44, GB 2
Headache mainly in the vertex: DU 20 or 23, extra point Si Shen Cong
Mainly neck pain: bladder (BL) 10, 60, or 62; DU 14 or 19; small intestine (SI) 3 or 6
Holocephalic pain with fatigue: extra point Taiyang, spleen (SP) 6 or 9, ST 36 or 40, Ren Mai (REN) 12
Worse with wet or cold weather: LI 4, DU 14, GB 3, Sanjiao (SJ) 6, GB 39
Modalities wind, dampness, cold: LI 4, DU 14, SJ 6, GB 34
Modalities cold, wind: LI 4, lung (LU) 7, SJ 5, DU 14
Outcome measurement
All patients filled in headache diaries in the four weeks before randomisation (baseline phase), the 12 weeks after randomisation, and weeks 21 to 24 after randomisation. In addition, we asked patients to fill in a pain questionnaire before treatment, after 12 weeks, and after 24 weeks.6 This included the following validated scales: the German version of the pain disability index,7 a scale for assessing sensoric and affective aspects of pain (Schmerzempfindungs-Skala SES),8 the ADS depression scale,9 and the German version of the SF-36 to assess health related quality of life.10 The primary outcome measure was the difference in number of days with headache between the four weeks before randomisation (baseline phase) and weeks nine to 12 after randomisation.
To test blinding to treatment and assess the credibility of the different treatment methods, patients filled in a credibility questionnaire after the third acupuncture session.11 At the end of the study, patients were asked whether they thought that they had received acupuncture following the principles of Chinese medicine or the other type of acupuncture.
Statistical methods
We based confirmatory testing of the primary outcome measure and all main analyses (with SPSS 11.5) on the intention to treat population and used all available data. We used SOLAS 3.0 (Statistical Solutions, Cork, Ireland) to do sensitivity analyses for the primary outcome measure, replacing missing data with baseline values or multiple imputation. We tested a priori ordered two sided null hypotheses by using Student's t test (significance level 0.05). In the first step we investigated whether acupuncture reduced the number of days with headache more than no treatment, and in the second step (only if the first null hypothesis was rejected) we investigated whether acupuncture was more efficacious than minimal acupuncture. We give exploratory analyses (analysis of covariance adjusting for baseline differences and 2 tests) for predefined secondary outcome measures. We did an additional per protocol analysis including only patients without major protocol violations until week 12.
We made the original sample size calculation for one sided testing. Under this premise we planned the study to have 80% power to detect a group difference of two days with headache assuming a standard deviation of five days (thus an effect size of 0.4) and a 20% dropout rate.4 However, we later decided to use two sided testing to comply better with common standards. Before starting the analysis, and on the basis of the recommendation of the ethical review board, we decided to exclude the data from one centre that had included 26 patients, owing to repeated severe protocol deviations and the suspicion of data manipulation in some patients. We decided to do a sensitivity analysis including this centre's data.
Box 2: Minimal acupuncture points used in the trial
"Deltoideus"—in the middle of the line insertion of M deltoideus (LI 14) and acromion
"Upper arm"—2 cun laterally of LU 3
"Forearm"—1 cun ulnar of the proximal third of the line between heart (HE) 3 and HE 7
"Scapula"—1 cun laterally of the lower scapular edge
"Spina iliaca"—2 cun above spina iliaca anterior superior in vertical line to the arch of left ribs
"Back I"—5 cun laterally of the spine of lumbar vertebrum IV
"Back II"—5 cun laterally of the spine of lumbar vertebrum V
"Upper leg I"—6 cun above the upper edge of the patella (between the spleen and stomach meridians)
"Upper leg II"—4 cun above the upper edge of the patella
"Upper leg III"—2 cun dorsally of GB 31 (avoiding bladder meridian)
A cun is defined according to the rules of traditional acupuncture as the width of the interphalangeal joint of the patient's thumb
Results
Participants, treatment, and blinding
Between March 2002 and January 2004, approximately 2700 patients with headache expressed an interest in participating in the study; 524 entered the four week baseline period, and 296 patients recruited in 29 outpatient centres were randomised (fig 1). As described above, we excluded from the main analysis one trial centre with 26 patients, leaving 270 patients in the intention to treat population (132 acupuncture, 63 minimal acupuncture, 75 waiting list).
Fig 1 Flowchart of trial (ITT=intention to treat; MOM=main outcome measure; PP=per protocol). *Before starting analyses the data from one trial centre were excluded from the main analysis owing to severe protocol violations and suspicion of data manipulation; the data were included in an additional sensitivity analysis (see methods section)
Groups were comparable at baseline in most respects (table 1). However, we observed some differences in previous use of acupuncture and in parts of the pain questionnaire. After three sessions, patients rated the credibility of acupuncture and minimal acupuncture very highly and very similarly (table 2). At the end of the study, patients' guesses as to their allocation status did not differ significantly between groups, but patients in the acupuncture group guessed their allocation correctly slightly more often than did patients in the minimal acupuncture group.
Table 1 Baseline characteristics
Table 2 Questions about credibility of treatment after third treatment session (rating scale with 0=disagreement and 6=maximal agreement) and guess at end of week 24 as to which type of acupuncture had been received
Effectiveness
From baseline to week 9-12, the number of days with headache decreased by 7.2 (SD 6.5) days in the acupuncture group compared with 6.6 (SD 6.0) days in the minimal acupuncture group and 1.5 (SD 3.7) days in the waiting list group (difference: acupuncture v minimal acupuncture, 0.6 days, 95% confidence interval -1.5 to 2.6 days, P = 0.58; acupuncture v waiting list, 5.7 days, 4.2 to 7.2 days, P < 0.001) (fig 2). Results were very similar in sensitivity analyses and in the per protocol analysis. The proportion of responders (at least 50% reduction in headache days, counting all patients with missing data as non-responders) was 46% in the acupuncture group, 35% in the minimal acupuncture group, and 4% in the waiting list group (exploratory P values 0.163 for acupuncture v minimal acupuncture and < 0.001 for acupuncture v waiting list).
Fig 2 Mean (95% confidence interval) number of days with headache. Patients in the waiting list group received acupuncture after week 12 (dotted bars)
Compared with the waiting list control group, patients receiving acupuncture or minimal acupuncture fared significantly better for most secondary outcome measures; however, we found no significant differences between the acupuncture and the minimal acupuncture group (table 3). Differences compared with waiting list became apparent in the headache diary after the first four weeks of treatment and increased until week 12 (fig 2).
Table 3 Secondary outcome measures after treatment
The improvements seen in the acupuncture and minimal acupuncture group persisted during the follow-up period (table 4). The patients in the waiting list group who received acupuncture in weeks 13-20 also showed significant improvements after treatment, although not to the same extent as the patients who had received immediate treatment.
Table 4 Secondary outcome measures at follow-up
Safety
Within the 24 weeks after randomisation a total of three serious adverse events (two acupuncture, one waiting list) were documented. All cases were hospital stays considered unrelated to the study (two diagnostic interventions, one elective surgery). Twenty three patients in the acupuncture group reported a total of 30 side effects compared with 11 patients in the minimal acupuncture group reporting a total of 14 side effects. The most commonly reported side effects were triggering of headache or other pain, haematoma, and dizziness.
Discussion
International Headache Society. ICH-10 guide for headaches. Cephalalgia 1997;17(suppl 19): 1-82.
Schwartz BS, Stewart WF, Simon D, Lipton RB. Epidemiology of tension-type headache. JAMA 1998;279: 381-3.
Melchart D, Linde K, Fischer P, White A, Allais G, Vickers A, et al. Acupuncture for recurrent headaches: a systematic review of randomized controlled trials. Cephalalgia 1999;19: 779-86.
Melchart D, Linde K, Streng A, Reitmayr S, Hoppe A, Brinkhaus B, et al. Acupuncture randomized trials (ART) in patients with migraine or tension-type headache—design and protocols. Forsch Komplement?rmed Klass Naturheilkd 2003;10: 179-84.
Pfaffenrath V, Brune K, Diener HC, Gerber WD, G?bel H. Schmerz 1998;12: 156-70.
Nagel B, Gerbershagen HU, Lindena G, Pfingsten M. Schmerz 2002;16: 263-70.
Dillmann U, Nilges P, Saile E, Gerbershagen HU. Schmerz 1994;8: 100-10.
Geissner E, Schulte A. Die Schmerzempfindungsskala (SES). Weinheim: Beltz, 1991.
Hautzinger M, Bailer M. Allgemeine Depressionsskala (ADS). Die deutsche Version des CES-D. Weinheim: Beltz, 1991.
Bullinger M, Kirchberger I. SF-36 Fragebogen zum Gesundheitszustand. G?ttingen: Hogrefe, 1998.
Vincent C. Credibility assessments in trials of acupuncture. Compl Med Res 1990;4: 8-11.
Karst M, Reinhard M, Thum P, Wiese B, Rollnik J, Fink M. Needle acupuncture in tension-type headache: a randomized, placebo-controlled study. Cephalalgia 2001;21: 637-42.
Tavola T, Gala C, Conte G, Invernizzi G. Traditional Chinese acupuncture in tension-type headache: a controlled study. Pain 1992;48: 325-9.
Carlsson J, Fahlcrantz A, Augustinsson LE. Muscle tenderness in tension headache treated with acupuncture or physiotherapy. Cephalalgia 1990;10: 131-41.
Hansen PE, Hansen JH. Acupuncture treatment of chronic tension headache—a controlled cross-over trial. Cephalalgia 1985;5: 137-42.
White AR, Resch KL, Chan JCK, Norris CD, Modi SK, Patel JN, et al. Acupuncture for episodic tension-type headache: a multicentre randomized controlled trial. Cephalalgia 2000;20: 632-7.
Xue CCL, Dong L, Polus B, English RA, Zheng Z, da Costa C, et al. Electroacupuncture for tension-type headache on distal acupoints only: a randomized, controlled cross-over trial. Headache 2004;44: 333-41.
Schoenen J. Guidelines for trials of drug treatments in tension-type headache. Cephalalgia. 1995;15: 165-79.
Vickers AJ, Rees RW, Zollman CE, McCarney R, Smith C, Ellis N, et al. Acupuncture for chronic headache in primary care: large, pragmatic, randomised trial. BMJ 2004;328: 744-7.
Irnich D, Beyer A. Schmerz 2002;16: 93-102.
Kaptchuk TJ, Goldman P, Stone DA, Stason WB. Do medical devices have enhanced placebo effects? J Clin Epidemiol 2000;53: 786-92.
Kaptchuk TJ. The placebo effect in alternative medicine: can the performance of a healing ritual have clinical significance? Ann Intern Med 2002;136: 817-25.
Bogaards MC, ter Kuile MM. Treatment of recurrent tension headache: a meta-analytic review. Clin J Pain 1994;10: 174-90.
Hrobjartsson A, G?tzsche PC. Is the placebo powerless? An analysis of clinical trials comparing placebo with no treatment. N Engl J Med 2001;344: 1594-602.(Dieter Melchart, director, researcher1,7)
Correspondence to: K Linde Klaus.Linde@lrz.tu-muenchen.de
Objective To investigate the effectiveness of acupuncture compared with minimal acupuncture and with no acupuncture in patients with tension-type headache.
Design Three armed randomised controlled multicentre trial.
Setting 28 outpatient centres in Germany.
Participants 270 patients (74% women, mean age 43 (SD 13) years) with episodic or chronic tension-type headache.
Interventions Acupuncture, minimal acupuncture (superficial needling at non-acupuncture points), or waiting list control. Acupuncture and minimal acupuncture were administered by specialised physicians and consisted of 12 sessions per patient over eight weeks.
Main outcome measure Difference in numbers of days with headache between the four weeks before randomisation and weeks 9-12 after randomisation, as recorded by participants in headache diaries.
Results The number of days with headache decreased by 7.2 (SD 6.5) days in the acupuncture group compared with 6.6 (SD 6.0) days in the minimal acupuncture group and 1.5 (SD 3.7) days in the waiting list group (difference: acupuncture v minimal acupuncture, 0.6 days, 95% confidence interval -1.5 to 2.6 days, P = 0.58; acupuncture v waiting list, 5.7 days, 3.9 to 7.5 days, P < 0.001). The proportion of responders (at least 50% reduction in days with headache) was 46% in the acupuncture group, 35% in the minimal acupuncture group, and 4% in the waiting list group.
Conclusions The acupuncture intervention investigated in this trial was more effective than no treatment but not significantly more effective than minimal acupuncture for the treatment of tension-type headache.
Trial registration number ISRCTN9737659.
Tension-type headache is essentially defined as bilateral headache of a pressing or tightening quality without a known medical cause.1 Tension-type headache is classified as episodic if it occurs on less than 15 days a month and as chronic if it occurs more often.1 A survey from the United States found a one year prevalence of 38% for episodic tension-type headache and 2% for chronic tension-type headache.2 Acupuncture is widely used for the treatment of tension-type headache, but its effectiveness is controversial.3 In the acupuncture randomised trial in tensiontype headache (ART-TTH), we investigated whether acupuncture reduced the frequency of headache more effectively than did minimal acupuncture (superficial needling at non-acupuncture points) or no acupuncture in patients with tension-type headache.
Methods
Protocol, design, and randomisation
ART-TTH was a randomised multicentre trial comparing acupuncture, minimal acupuncture, and a no acupuncture waiting list condition. Minimal acupuncture served as a sham intervention; we included the additional no acupuncture waiting list control because minimal acupuncture is not a physiologically inert placebo. Patients were blinded to treatment in the acupuncture and minimal acupuncture arms of the study. Two blinded evaluators analysed headache diaries. The methods of the trial have been described in detail elsewhere.4
After a baseline phase of four weeks, we used a centralised telephone randomisation procedure (random list generated with sample size 2.0 by the statistician) to randomise patients, stratified by centre (block size 12 unknown to trial physicians), in a 2:1:1 ratio (acupuncture:minimal acupuncture:waiting list). We used the 2:1:1 ratio to facilitate recruitment and increase the compliance of trial physicians. All study participants provided written, informed consent, and the study conformed to common guidelines for clinical trials (Declaration of Helsinki, ICH-GCP, including certification by external audit).
Participants
Inclusion criteria were a diagnosis of episodic or chronic tension-type headache according to the criteria of the International Headache Society,1 at least eight days with headache a month in the previous three months and in the baseline period, age 18-65 years, duration of symptoms at least 12 months, completed baseline headache diary, and written informed consent. Main exclusion criteria were additional migraine headache, secondary headaches, start of headaches after age 50, use of analgesics on more than 10 days a month, prophylactic headache treatment with drugs during the previous four weeks, and any acupuncture treatment during the previous 12 months or at any time if done by the participating trial physician. Most participants were recruited through reports in local newspapers; a minority were patients who spontaneously contacted trial centres.
Interventions
We developed the study interventions in a consensus process with German acupuncture experts and societies.4 Physicians trained (at least 140 hours, median 500 hours) and experienced (median 10 years) in acupuncture delivered the interventions. Both the acupuncture and minimal acupuncture treatments consisted of 12 sessions of 30 minutes, given over eight weeks (preferably two sessions in each of the first four weeks, followed by one session a week in the remaining four weeks).
Acupuncture treatment was semistandardised. All patients were treated at "basic" points bilaterally unless explicit reasons for not doing so were given; additional points could be chosen individually (box 1). We instructed physicians to achieve "de qi" (an irradiating feeling considered to be indicative of effective needling) if possible and to stimulate needles manually at least once during each session. The total number of needles was limited to 25 per session.
The number, length, and frequency of the sessions in the minimal acupuncture group were the same as for the acupuncture group. In each session, physicians needled at least five out of 10 predefined distant non-acupuncture points (box 2) bilaterally (at least 10 needles) and superficially using fine needles. Physicians avoided "de qi" and manual stimulation of the needles.
Patients in the waiting list control group did not receive any prophylactic treatment for their headaches for a period of 12 weeks after randomisation. After that time, they received 12 sessions of the acupuncture treatment described above.
All patients were allowed to treat acute headaches as needed. Treatment was supposed to follow current guidelines5 and had to be documented in the headache diary.
Patients were informed with respect to acupuncture and minimal acupuncture as follows: "In this study, different types of acupuncture will be compared. One type is similar to the acupuncture treatment used in China. The other type does not follow the principles of traditional Chinese medicine, but has also been associated with positive outcomes in clinical studies."
Box 1: Acupuncture points used in the trial
All physicians used sterile, disposable, single use needles but were free in their choice of length and diameter of needle
Basic points
Gall bladder (GB) 20
GB 21
Liver (LIV) 3
Optional points
Mainly frontal headache: large intestine (LI) 4, Du Mai (DU) 23, extra points Yintang and Taiyang, stomach (ST) 44, GB 2
Headache mainly in the vertex: DU 20 or 23, extra point Si Shen Cong
Mainly neck pain: bladder (BL) 10, 60, or 62; DU 14 or 19; small intestine (SI) 3 or 6
Holocephalic pain with fatigue: extra point Taiyang, spleen (SP) 6 or 9, ST 36 or 40, Ren Mai (REN) 12
Worse with wet or cold weather: LI 4, DU 14, GB 3, Sanjiao (SJ) 6, GB 39
Modalities wind, dampness, cold: LI 4, DU 14, SJ 6, GB 34
Modalities cold, wind: LI 4, lung (LU) 7, SJ 5, DU 14
Outcome measurement
All patients filled in headache diaries in the four weeks before randomisation (baseline phase), the 12 weeks after randomisation, and weeks 21 to 24 after randomisation. In addition, we asked patients to fill in a pain questionnaire before treatment, after 12 weeks, and after 24 weeks.6 This included the following validated scales: the German version of the pain disability index,7 a scale for assessing sensoric and affective aspects of pain (Schmerzempfindungs-Skala SES),8 the ADS depression scale,9 and the German version of the SF-36 to assess health related quality of life.10 The primary outcome measure was the difference in number of days with headache between the four weeks before randomisation (baseline phase) and weeks nine to 12 after randomisation.
To test blinding to treatment and assess the credibility of the different treatment methods, patients filled in a credibility questionnaire after the third acupuncture session.11 At the end of the study, patients were asked whether they thought that they had received acupuncture following the principles of Chinese medicine or the other type of acupuncture.
Statistical methods
We based confirmatory testing of the primary outcome measure and all main analyses (with SPSS 11.5) on the intention to treat population and used all available data. We used SOLAS 3.0 (Statistical Solutions, Cork, Ireland) to do sensitivity analyses for the primary outcome measure, replacing missing data with baseline values or multiple imputation. We tested a priori ordered two sided null hypotheses by using Student's t test (significance level 0.05). In the first step we investigated whether acupuncture reduced the number of days with headache more than no treatment, and in the second step (only if the first null hypothesis was rejected) we investigated whether acupuncture was more efficacious than minimal acupuncture. We give exploratory analyses (analysis of covariance adjusting for baseline differences and 2 tests) for predefined secondary outcome measures. We did an additional per protocol analysis including only patients without major protocol violations until week 12.
We made the original sample size calculation for one sided testing. Under this premise we planned the study to have 80% power to detect a group difference of two days with headache assuming a standard deviation of five days (thus an effect size of 0.4) and a 20% dropout rate.4 However, we later decided to use two sided testing to comply better with common standards. Before starting the analysis, and on the basis of the recommendation of the ethical review board, we decided to exclude the data from one centre that had included 26 patients, owing to repeated severe protocol deviations and the suspicion of data manipulation in some patients. We decided to do a sensitivity analysis including this centre's data.
Box 2: Minimal acupuncture points used in the trial
"Deltoideus"—in the middle of the line insertion of M deltoideus (LI 14) and acromion
"Upper arm"—2 cun laterally of LU 3
"Forearm"—1 cun ulnar of the proximal third of the line between heart (HE) 3 and HE 7
"Scapula"—1 cun laterally of the lower scapular edge
"Spina iliaca"—2 cun above spina iliaca anterior superior in vertical line to the arch of left ribs
"Back I"—5 cun laterally of the spine of lumbar vertebrum IV
"Back II"—5 cun laterally of the spine of lumbar vertebrum V
"Upper leg I"—6 cun above the upper edge of the patella (between the spleen and stomach meridians)
"Upper leg II"—4 cun above the upper edge of the patella
"Upper leg III"—2 cun dorsally of GB 31 (avoiding bladder meridian)
A cun is defined according to the rules of traditional acupuncture as the width of the interphalangeal joint of the patient's thumb
Results
Participants, treatment, and blinding
Between March 2002 and January 2004, approximately 2700 patients with headache expressed an interest in participating in the study; 524 entered the four week baseline period, and 296 patients recruited in 29 outpatient centres were randomised (fig 1). As described above, we excluded from the main analysis one trial centre with 26 patients, leaving 270 patients in the intention to treat population (132 acupuncture, 63 minimal acupuncture, 75 waiting list).
Fig 1 Flowchart of trial (ITT=intention to treat; MOM=main outcome measure; PP=per protocol). *Before starting analyses the data from one trial centre were excluded from the main analysis owing to severe protocol violations and suspicion of data manipulation; the data were included in an additional sensitivity analysis (see methods section)
Groups were comparable at baseline in most respects (table 1). However, we observed some differences in previous use of acupuncture and in parts of the pain questionnaire. After three sessions, patients rated the credibility of acupuncture and minimal acupuncture very highly and very similarly (table 2). At the end of the study, patients' guesses as to their allocation status did not differ significantly between groups, but patients in the acupuncture group guessed their allocation correctly slightly more often than did patients in the minimal acupuncture group.
Table 1 Baseline characteristics
Table 2 Questions about credibility of treatment after third treatment session (rating scale with 0=disagreement and 6=maximal agreement) and guess at end of week 24 as to which type of acupuncture had been received
Effectiveness
From baseline to week 9-12, the number of days with headache decreased by 7.2 (SD 6.5) days in the acupuncture group compared with 6.6 (SD 6.0) days in the minimal acupuncture group and 1.5 (SD 3.7) days in the waiting list group (difference: acupuncture v minimal acupuncture, 0.6 days, 95% confidence interval -1.5 to 2.6 days, P = 0.58; acupuncture v waiting list, 5.7 days, 4.2 to 7.2 days, P < 0.001) (fig 2). Results were very similar in sensitivity analyses and in the per protocol analysis. The proportion of responders (at least 50% reduction in headache days, counting all patients with missing data as non-responders) was 46% in the acupuncture group, 35% in the minimal acupuncture group, and 4% in the waiting list group (exploratory P values 0.163 for acupuncture v minimal acupuncture and < 0.001 for acupuncture v waiting list).
Fig 2 Mean (95% confidence interval) number of days with headache. Patients in the waiting list group received acupuncture after week 12 (dotted bars)
Compared with the waiting list control group, patients receiving acupuncture or minimal acupuncture fared significantly better for most secondary outcome measures; however, we found no significant differences between the acupuncture and the minimal acupuncture group (table 3). Differences compared with waiting list became apparent in the headache diary after the first four weeks of treatment and increased until week 12 (fig 2).
Table 3 Secondary outcome measures after treatment
The improvements seen in the acupuncture and minimal acupuncture group persisted during the follow-up period (table 4). The patients in the waiting list group who received acupuncture in weeks 13-20 also showed significant improvements after treatment, although not to the same extent as the patients who had received immediate treatment.
Table 4 Secondary outcome measures at follow-up
Safety
Within the 24 weeks after randomisation a total of three serious adverse events (two acupuncture, one waiting list) were documented. All cases were hospital stays considered unrelated to the study (two diagnostic interventions, one elective surgery). Twenty three patients in the acupuncture group reported a total of 30 side effects compared with 11 patients in the minimal acupuncture group reporting a total of 14 side effects. The most commonly reported side effects were triggering of headache or other pain, haematoma, and dizziness.
Discussion
International Headache Society. ICH-10 guide for headaches. Cephalalgia 1997;17(suppl 19): 1-82.
Schwartz BS, Stewart WF, Simon D, Lipton RB. Epidemiology of tension-type headache. JAMA 1998;279: 381-3.
Melchart D, Linde K, Fischer P, White A, Allais G, Vickers A, et al. Acupuncture for recurrent headaches: a systematic review of randomized controlled trials. Cephalalgia 1999;19: 779-86.
Melchart D, Linde K, Streng A, Reitmayr S, Hoppe A, Brinkhaus B, et al. Acupuncture randomized trials (ART) in patients with migraine or tension-type headache—design and protocols. Forsch Komplement?rmed Klass Naturheilkd 2003;10: 179-84.
Pfaffenrath V, Brune K, Diener HC, Gerber WD, G?bel H. Schmerz 1998;12: 156-70.
Nagel B, Gerbershagen HU, Lindena G, Pfingsten M. Schmerz 2002;16: 263-70.
Dillmann U, Nilges P, Saile E, Gerbershagen HU. Schmerz 1994;8: 100-10.
Geissner E, Schulte A. Die Schmerzempfindungsskala (SES). Weinheim: Beltz, 1991.
Hautzinger M, Bailer M. Allgemeine Depressionsskala (ADS). Die deutsche Version des CES-D. Weinheim: Beltz, 1991.
Bullinger M, Kirchberger I. SF-36 Fragebogen zum Gesundheitszustand. G?ttingen: Hogrefe, 1998.
Vincent C. Credibility assessments in trials of acupuncture. Compl Med Res 1990;4: 8-11.
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