Efficacy of Acupuncture is Non-Inferior To NRT for Tobacco Cessation: Results of A Prospective, Randomized, Active-Controlled Open-Label Trial

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1 Accepted Manuscript Efficacy of Acupuncture is Non-Inferior To NRT for Tobacco Cessation: Results of A Prospective, Randomized, Active-Controlled Open-Label Trial Ying-ying Wang, MD, PhD, Zhao Liu, MD, PhD, Yuan Wu, MSc, Li Yang, MSc, Langtao Guo, MSc, Hao-bin Zhang, MSc, Jin-sheng Yang, MD, PhD PII: S (17) DOI: /j.chest Reference: CHEST 1443 To appear in: CHEST Received Date: 12 July 2017 Revised Date: 29 September 2017 Accepted Date: 6 November 2017 Please cite this article as: Wang Yy, Liu Z, Wu Y, Yang L, Guo Lt, Zhang Hb, Yang Js, on behalf of thechinese Acupuncture for Tobacco Cessation Research Team, Efficacy of Acupuncture is Non-Inferior To NRT for Tobacco Cessation: Results of A Prospective, Randomized, Active-Controlled Open-Label Trial, CHEST (2017), doi: /j.chest This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

2 Efficacy of Acupuncture is Non-Inferior To NRT for Tobacco Cessation: Results of A Prospective, Randomized, Active-Controlled Open-Label Trial WANG Ying-ying, MD, PhD 1& ; LIU Zhao, MD, PhD 2, 3& ; WU Yuan, MSc 1 ; YANG Li, MSc 1 ; GUO Lang-tao, MSc 4 ; ZHANG Hao-bin, MSc 5 ; YANG Jin-sheng, MD, PhD 1 ; on behalf of the Chinese Acupuncture for Tobacco Cessation Research Team (1. Institute of Acupuncture and Moxibustion, China Academy of Chinese Medical Sciences, Beijing , China; 2. Tobacco Medicine and Tobacco Cessation Centre, China-Japan Friendship Hospital, Beijing , China; 3. WHO Collaborating Centre for Tobacco Cessation and Respiratory Diseases Prevention, Beijing , China; 4. Department of Acupuncture and Moxibustion, Shaanxi TCM Hospital, Xi an , Shaanxi Province, China; 5. College of Acupuncture and Moxibustion, Shaanxi University of TCM, Xi an , Shaanxi Province, China) &These authors contributed equally to this work and should be considered co-first authors. Competing interests The authors declare no potential conflict of interests with respect to the research, authorship, and/or publication of this paper. Funding This paper was supported by the Special Scientific Research Fund of Traditional Chinese Medicine Profession of China (Project No ). Trial registration Chinese Clinical Trial Registry (ChiCTR-TRC ). 1

3 Acknowledgements We thank all the patients and their families for their participation in this trial. Corresponding author: YANG Jin-sheng (1964- ), M.D. Research area: standardization and clinical evaluation of acupuncture. Authors' Contributions YANG Jin-sheng (guarantor of the entire manuscript) had full access to all the data and took responsibility for the integrity of the data and the accuracy of the data analysis. YANG Jin-sheng and WANG Ying-ying contributed to the design and management of the trial. LIU Zhao drafted the manuscript. WU Yuan, YANG Li delivered the guidance and curriculum to the acupuncturists. LIU Zhao, WU Yuan, ZHANG Hao-bin and GUO Lang-tao participated in the clinical treatment and data collection in this trial. Role of the Funder/Sponsor: The trial sponsor had no role in the design and conduct of the trial; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication. ABSTRACT Objective We designed and conducted this multicenter randomized active-controlled open-label trial to evaluate the efficacy of acupuncture, auricular point pressing and nicotine replacement therapy (NRT) on tobacco cessation in Chinese population. Methods This RCT was conducted at 7 hospitals in China between October of 2013 to February of Eligible participants were recruited and randomly assigned to receive acupuncture or 2

4 auricular point pressing or NRT via a central randomization system with a 1:1:1 ratio. All treatment was given for totally 8 weeks and follow-up visit was 16 weeks. The primary outcome measure was carbon monoxide (CO) confirmed 24-hour point abstinence rate (<10 ppm), 24 weeks after quit day. Results A total of 300 participants were recruited and 195 participants finished with a drop-out rate of 35.00%. Two cases of adverse events in acupuncture group and two cases in NRT group were observed. The CO confirmed 24-hour point abstinence rate was 43.00% at 24 weeks in acupuncture group, which was similar to 44.00% in NRT group (P>0.05), but significantly higher than 30.00% in auricular point group (P<0.05). At 24 weeks, Fagerström Nicotine Dependence Test (FTND) and Minnesota Nicotine Withdrawal Scale (MNWS) in acupuncture group were significantly lower than those in auricular point group and in NRT group (P<0.05). The Kaplan-Meier analysis showed the time to relapse for acupuncture (44.12 days) was insignificantly longer than NRT (41.18 days), but significantly longer than auricular point pressing (29.53 days). Conclusion We found acupuncture was safe and a possible treatment for tobacco cessation, but it required further study to establish its role. Funding Special Scientific Research Fund of Traditional Chinese Medicine Profession of China (Project No ). 3

5 Introduction Tobacco use is a significant threat to human health and social development, which is estimated to cause approximately 6 million global deaths each year [1]. It is one of the main risk factors driving the growing epidemic of non-communicable diseases (NCDs). Currently a staggering 44% of the world s cigarettes are smoked in China [2], and one million people die of tobacco-related diseases every year [3]. The treatments for tobacco cessation include varenicline, bupropion, nicotine replacement therapy, behavioral support and other treatments [4]. However, stopping smoking is difficult, and complementary therapies, such as acupuncture, are popular and frequently used, particularly in China. Acupuncture was firstly used in tobacco cessation in Hong Kong in 1973 [5]. Following this inspiration, a great number of studies explored the efficacy of acupuncture on tobacco cessation. However, in spite of its high acceptance, the overall efficacy of acupuncture on tobacco cessation is controversial. Available research [6-7] suggests that acupuncture has the potential to assist smokers to quit or reduce smoking. Our previous clinical studies involving 5202 participants found acupuncture was safe for tobacco cessation with abstinence rate of 34.0% in Week 8 and 18.4% in Week 52, respectively [8-9]. On the other hand, a meta-analysis reported by the Cochrane Library [10] showed no significant difference between acupuncture and placebo in tobacco cessation, and suggested further research should include adequate sample size, appropriate randomization and control method, highly trained and experienced acupuncturists, longer time of follow-up and biochemical validation of tobacco cessation. In order to provide more clinical evidence regarding acupuncture for tobacco cessation, head-to-head evaluation was needed in two aspects. On one hand, acupuncture could further be 4

6 divided into acupuncture, auricular point pressing, cupping therapy, Gua Sha therapy and so on; among them, acupuncture and auricular point pressing were mostly used for tobacco cessation, but the efficacy differences of two remain unclear. On the other hand, few clinical trials have directly compared the efficacies between acupuncture and medications [11]. Therefore, we designed and conducted this multicenter randomized active-controlled open-label trial to head-to-head evaluate the efficacy of acupuncture, auricular point pressing and nicotine replacement therapy (NRT) on tobacco cessation in a Chinese population. Methods Trial design This was a multicenter randomized active-controlled open-label trial conducted at 7 hospitals in China (Supplementary Table 1). Trial sites included academic center, hospital and outpatient clinics. This trial was consisted of a preparation period, 8-week treatment period and 16-week follow-up period (Supplementary Figure 1). This trial was approved by China Ethics Committee of Registering Clinical Trials (ChiECRCT ), and registered in Chinese Clinical Trial Registry (ChiCTR-TRC ). Participants Eligible participants were recruited via trial sites, local newspaper, hotline of smoking cessation, community events, websites and recommendation from other medical institutions. The participants were included if they voluntarily participated in this trial; they were daily smokers and were motivated to quit, aged 18 to 70 years; smoked more than 1 year; smoked an average of ten or more cigarettes per day during previous year; signed the informed consent; positive results of urine nicotine test at screening. The participants were excluded if they had 5

7 mental diseases, serious cardiovascular diseases, apoplexy or nervous system diseases, had disturbances of blood coagulation, or were pregnant, or use of acupuncture, auricular point pressing or NRT within past 30 days. The trial adhered to the Declaration of Helsinki. All participants signed informed consent and received financial compensation for trial participation time and travel expenses at each trial site. Randomization and blind According to the trial design, eligible participants were randomly assigned to receive acupuncture or auricular point pressing or NRT via a central randomization system. This central randomization system was based on computer telephone integration (CTI) technology. The researcher input the name of participants in the system to obtain subject identification number (SIN), and the system allocated the participants into three groups with 1:1:1 ratio by using stratified block randomization. The randomization sequences were generated by using Proc Plan in SAS, version 9.3 (SAS Institute), with the trial sites as the stratification factor and the block length as 5. Due to the obvious differences among three types of treatment, only outcome assessors and statisticians were blinded to treatment allocation. Quit date According to the recommendation of China Clinical Guidelines for Tobacco Cessation (2015 edition) [12], participants set a target quit date within 1 week after randomization Quality control All the acupuncturists in this trial were certified by State Administration of Traditional Chinese Medicine of China with clinical experience no less than 4 years; they received guidance 6

8 and curriculum from Institute of Acupuncture and Moxibustion, China Academy of Chinese Medical Sciences to guarantee the consistency of acupuncture treatment. Each acupuncture treatment was performed by at least one acupuncturist and one researcher, whereas acupuncturist was responsible for the treatment while researcher recorded the Case Report Form to guarantee the accuracy of the trial. Interventions The participants in the acupuncture group received acupuncture at Baihui (GV 20), Lieque (LU 7), Hegu (LI 4), Zusanli (ST 36), Sanyinjiao (SP 6) and Taichong (LR 3) (Figure 1), Yintang (EX-HN3) was added if there were symptoms of cough, running nose, dry eyes, etc., while Neiguan (PC 6) was added if there were symptoms of dysphoria, melancholy, insomnia, etc. Before acupuncture, the participants were in supine position to expose the acupoints. After skin disinfection, 0.25mm 40mm disposable sterile needles (purchased from Suzhou Medical Appliance Factory) were horizontally inserted at Baihui (GV 20) while vertically inserted at other acupoints with a depth of 25 to 50mm. The mild reinforcing and reducing technique was applied at all acupoints to achieve the arrival of (needle sensation). In order to augment the effects of acupuncture, electro-acupuncture was applied. The paired electrodes from the electro-acupuncture device (HuaTuo SDZ-III type) were attached to the needle handles at bilateral Lieque (LU 7) and Zusanli (ST 36). The electroacupuncture stimulation lasted for 30 minutes with a continuous wave of 15 Hz and a current intensity of 1 to 5 ma. After treatment, the needles were withdrawn quickly to avoid bleeding or hematoma. The acupuncture treatment lasted for 30 min, twice per week for 8 weeks. The participants in the auricular point pressing group received auricular point pressing at 7

9 Shenmen (TF 4), Neifenmi (CO 18), Pizhixia (AT 4), Jiaogan (AH 6), Fei (CO 14) and Wei (CO 4) (Figure 1). Kou (CO 1) was added if there were symptoms of nausea, while Zhiqiguan (CO 16) was added for cough phlegm. Before auricular point pressing, the participants were in sitting position to fully expose the auricular acupoints. After routine disinfection, the patch of vaccaria seeds with 2mm in diameter were used and stuck to different auricular acupoints. Each auricular acupoint was pressed for 1 min. In addition, participants were instructed to press each auricular acupuncture point for 20 s every 1 to 2 hours or whenever they had a craving for smoking. The treatment was twice per week for 8 weeks. The participants in the NRT group received NRT patch purchased from NOVARTIS, Switzerland. After removing the protective foil, the patch was applied to a clean, dry and intact area of skin (free from lotion, alcohol and ointment), preferably on trunk, or otherwise on the upper arm or hip, and pressed with palm for 10 seconds. To avoid local irritation of skin, a different site of application was chosen each day. Participants were asked to use 1 patch/day. For participants smoked less than 20 cigarettes per day, treatment started with 14 mg per day for 6 weeks, followed by 7 mg per day for 2 weeks; for those smoked more than 20 cigarettes per day, treatment started with 21 mg per day for 4 weeks, followed by 14 mg per day for 2 weeks and 7 mg per day for final 2 weeks. NRT patch was provided for 8 weeks. Outcome measures As recommended by the Guidelines [12], the primary outcome was carbon monoxide confirmed 24-hour point abstinence rate (<10 ppm), 24 weeks after quit day, using Bedfont Micro Smokerlyzers (Bedfont Scientific, Maidstone, UK). Secondary outcomes included adverse events, continuous abstinence rate from 12 weeks to 24 weeks, Fagerström Nicotine Dependence Test 8

10 (FTND) and Minnesota Nicotine Withdrawal Scale (MNWS) at baseline, 1 week, 2 weeks, 4 weeks, 8 weeks, 12 weeks and 24 weeks after quit date. Statistical analysis Based on the results of our previous study and pooled data from previous randomized controlled trials, the abstinence rates of acupuncture and NRT was estimated to be 30% and 40%, respectively; then a sample size of 100 participants per group was calculated to provide 80% power, assuming a 20% loss to follow-up. Intent to Treat (ITT) approach was applied in this trial, and the participants who were lost to contact were considered to be smokers. SPSS 19.0 statistical software was used for statistical analysis. < 0.05 was taken as statistical significance. The measurement data were represented with means ± standard deviation ( ± ). The -test was used for comparison which met Gaussian distribution and homogeneity of variance, while nonparametric test was used for comparison which did not met homogeneity of variance. Chi-square test was used for numeration data. The Kaplan-Meier curve was used for analyses of time to relapse. The logistic regression analysis was used to calculate the relationship between possible influence factors and abstinence results, represented with OR value and 95% credibility interval. Missing data on the primary outcome were imputed using the multiple imputation method under the missing-at-random assumption. The authors had no access to information that could identify individual participants during or after data collection. Results Between October of 2013 to February of 2016, 348 participants were screened for eligibility, of whom 300 were included into the baseline evaluation and randomly assigned to an acupuncture 9

11 group, an auricular point pressing group and a NRT group, 100 cases in each one. At 24 weeks, 42 participants in acupuncture group were lost to contact, which was significantly higher than 33 cases in auricular point pressing group and 30 cases in NRT group (P<0.05) (Figure 2). Baseline characteristics were similar among groups (Table 1). For the safety of interventions, only one case of fainting during acupuncture and one case of hematoma were observed in acupuncture group, and two cases of local irritation of skin were observed in NRT group. No participants quit the trial due to these adverse incidents. For the primary outcome, the CO confirmed 24-hour point abstinence rate was 43.00% at 24 weeks in acupuncture group, which was similar to 44.00% in NRT group (P>0.05), but significantly higher than 30.00% in auricular point group (P<0.05), indicating acupuncture and NRT had no difference of efficacy (Figure 3). Analysis between acupuncture group and NRT group indicated that the results were not driven by any particular subgroup (RR=0.99, 95% CI: 0.85, 1.14) (Figure 4). The secondary outcomes of continuous abstinence rate from 12 weeks to 24 weeks was 31.00% in acupuncture group, which was similar to 34% in NRT group (P>0.05), but significantly higher than 25% in auricular point group (P<0.05). For secondary outcomes of FTND, no significant differences were observed in three groups at baseline (P>0.05); at 8 weeks, the FTND was (4.92±2.98) points in acupuncture group, which was significantly lower than (5.82±3.22) points in auricular point group and (5.55±3.02) points in NRT group (P<0.05); at 24 weeks, the FTND was (4.69±3.01) points in acupuncture group, which was significantly lower than (5.78±3.28) points in auricular point group and (5.71±3.02) points in NRT group (P<0.05). For secondary outcomes of MNWS, at 1 week, the MNWS was (12.96±7.09) points in acupuncture group, which was significantly higher than (11.28±7.48) points in auricular 10

12 point group and (11.44±7.32) points in NRT group (P>0.05); at 8 weeks, the MNWS was (7.52±6.40) points in acupuncture group, which was insignificantly lower than (8.64±7.26) in auricular point group and (7.55±6.70) points in NRT group (P>0.05). The results of Kaplan-Meier analysis showed the time to relapse was days (95% CI: ) for acupuncture, which was insignificantly longer than days (95% CI ) of NRT but significantly longer than days (95% CI ) of auricular point pressing (Figure 5). Discussion With multiple treatment options available for tobacco cessation in China, head-to-head comparisons are needed to inform the choice of treatment. This multicenter randomized active-controlled open-label trial showed noninferiority of tobacco cessation between acupuncture and NRT, which were both superior to auricula point pressing. More importantly, this current result was similar with the results of our ongoing 7-year observational study in Hong Kong, indicating authenticity of acupuncture efficacy regardless of research settings. This present trial has followed suggested guidelines proposed by China Clinical Guidelines for Tobacco Cessation (2015 edition) [12] and STandards for Reporting Interventions in Clinical Trials of Acupuncture (STRICTA) [14] to minimize the risk of bias, including randomization, sample size calculation, biochemical validation of tobacco cessation, six-month follow-up and standardized manipulation of acupuncture, licensed and experienced acupuncturist to avoid possible bias between acupuncturists. Our results were consistent with previous studies of 27.15% by Wu [16], and was higher than 12.9% by Fritz [17], 4.1% by Aycicegi-Dinn [18] and 5% by Zhang [19]. The inconsistence of 11

13 conclusions was probably because although these studies claimed their treatment as acupuncture, the acupuncture settings were different, including acupuncture forms (needle type and electrical stimulation), selection of acupoints, technical skills, and treatment courses, which could affect the clinical effects of acupuncture and result in the inconsistence. Interestingly, we found the point abstinence rate in NRT group was increased rapidly from quit date to peak at 8 weeks, and then gradually reduced; on the contrary, the point abstinence rate in acupuncture group showed a different pattern: increased slowly but lasted longer. This indicated if more attention was paid within first weeks to guarantee the compliance of acupuncture, even with intensive psychological intervention and behavior support, a better results of tobacco cessation might be achieved. The possible mechanism of acupuncture for tobacco cessation remain unclear. In current trial, FTND and MNWS were significantly lower in acupuncture than those in auricular point pressing and NRT group. Regular stimulation of acupuncture affects the nerve systems that regulate neurotransmitters, including dopamine via GABA, b-endorphin and norepinephrine, and neural activity in the nucleus accumbens. It may also directly affect the desire to smoke. Moreover, our previous study [21] used functional neuroimaging technologies to investigate the neuroanatomical substrates of acupuncture on tobacco cessation, and identified ACC, insula, PFC, visual cortex and cerebellum as key brains area in tobacco cessation, and proposed the immediate effects of acupuncture on tobacco cessation was to improve the cognition function through ACC and insula circuit, leading to better execution function and impulsivity control. Future studies were needed to explore the neural mechanisms of long-term acupuncture. When treatments with similar safety and efficacy were options for tobacco cessation, the cost assumes greater importance in determining treatment choice. The cost to the patient of 12

14 acupuncture is less than that of NRT in China, which may make it a more desirable therapy in our trial setting but may won t apply to other settings. As such, we propose acupuncture be considered as one of the methods to help smokers quit. The limitations of this trial must be acknowledged. Firstly, although we had no difficulty in recruiting participants for this trial, high drop-out rate has been noted. Although previous studies indicated [22] high drop-out rate was a common complication of research into substance abuse, and was related to many environmental and personal factors not related to the long-term effect of acupuncture, it still could have affected results. Secondly, because more highly motivated participants were recruited in present trial, the results may overestimate the effects of the acupuncture as they would occur in real-world clinical practice. Thirdly, because this was an open-label trial, the outcome measures may have been influenced by expectations or biases of the participants or research staff. Lastly, quite a lot of subjects did not receive sufficient acupuncture because of busy life, job mobility or lack of acupuncture knowledge and it was possible that the culturally and linguistically tailored counseling contributed significantly to the outcomes. Therefore, it was suggested that public education regarding acupuncture for tobacco cessation should be prompted, such as providing community lessons, sending publicity materials of acupuncture, and explaining the theories and advantages of acupuncture. In addition, successful cases can be introduced so that more people can have a clear understanding about tobacco cessation with acupuncture. Conclusion To our knowledge, this was the most rigorous RCT to date to investigate the safety and efficacy of acupuncture for tobacco cessation in China. We found acupuncture was safe and a 13

15 possible treatment for tobacco cessation, but it required further study to establish its role. References 1 Ministry of Health of People s Republic of China. China Report on the Health Hazards of Smoking. Beijing, World Health Organization. The bill China cannot afford: health, economic and social costs of China s tobacco epidemic. Manila, Chen Z, Peto R, Zhou M, Iona A, Smith M, Yang L, Guo Y, Chen Y, Bian Z, Lancaster G, Sherliker P, Pang S, Wang H, Su H, Wu M, Wu X, Chen J, Collins R, Li L, China Kadoorie Biobank collaborative group. Contrasting male and female trends in tobacco-attributed mortality in China: evidence from successive nationwide prospective cohort studies. Lancet. 2015; 386 (10002): Benowitz NL. Nicotine addiction. N Engl J Med. 2010; 362: Abdullah AS, Hedley AJ, Chan SS, Ho WW, Lam TH, Hong Kong Council on Smoking and Health Smoking Cessation Health Centre Steering Group. Establishment and evaluation of a smoking cessation clinic in Hong Kong: a model for the future service provider. Public Health (Oxf). 2004; 26 (3): Castera P, Nguyen J, Gerlier JL. Is acupuncture beneficial in tobacco cessation, and is its effect specific? A meta analysis. Acupuncture & Moxibustion. 2002; 1 (4): Bilici M, Güven S, Köşker S, Şafak A, Semiz ÜB. Electroacupuncture Therapy in Nicotine Dependence: A Double Blind, Sham-Controlled Study. Noro Psikiyatr Ars. 2016; 53 (1): Ma E, Chan T, Zhang O, Yang JS, Wang YY, Li YC, Ho R, Lai C, Lam PY. Effectiveness of 14

16 acupuncture for smoking cessation in a Chinese population. Asia-Pacific Journal of Public Health. 2015; 27(2): NP2610 NP Wang YY, Liu Z, Wu Y, Zhang O, Chen M, Huang LL, He XQ, Wu GY, Yang JS. Acupuncture for Smoking Cessation in Hong Kong: A Prospective Multicenter Observational Study. Evid Based Complement Alternat Med. 2016; White AR, Rampes H, Liu JP, Stead LF, Campbell J. Acupuncture and related interventions for smoking cessation. Cochrane Database of Systematic Reviews. 2014; CD Liu Z, Wang Y, Wu Y, Yang J. Condition and effectiveness evaluation of acupuncture for smoking cessation. Chinese Acupuncture & Moxibustion. 2015; 35 (8): China National Health and Family Planning Commission. China Clinical Guidelines for Tobacco Cessation, WHO Regional Office for the Western Pacific, Acupuncture Point Locations in the Western Pacific Region, World Health Organization. Western Pacific Region, Beijing, MacPherson H, Altman DG, Hammerschlag R, Youping L, Taixiang W, White A, Moher D, STRICTA Revision Group. Revised STandards for Reporting Interventions in Clinical Trials of Acupuncture (STRICTA): Extending the CONSORT statement. J Evid Based Med. 2010; 3 (3): Hyun MK, Lee MS, Kang K, Choi SM. Body acupuncture for nicotine withdrawal symptoms: a randomized placebo-controlled trial. Evidence-Based Complementary and Alternative Medicine. 2010; 7 (2): Wu TP, Chen FP, Liu JY, Lin MH, Hwang SJ. A randomized controlled clinical trial of auricular acupuncture in smoking cessation. J Chin Med Assoc. 2007; 70 (8):

17 17 Fritz DJ, Carney RM, Steinmeyer B, Ditson G, Hill N, Zee-Cheng J. The efficacy of auriculotherapy for smoking cessation: a randomized, placebo-controlled trial. J Am Board Fam Med. 2013; 26 (1): Aycicegi-Dinn A, Dinn W. Efficacy of an alternative smoking cessation treatment. J Addict Dis. 2011; 30 (4): Zhang AL, Di YM, Worsnop C, May BH, Da Costa C, Xue CC. Ear acupressure for smoking cessation: a randomised controlled trial. Evid Based Complement Alternat Med. 2013: Kang OS, Kim SY, Jahng GH, Kim H, Kim JW, Chung SY, Kim JW, Yang SI, Park HJ, Lee H, Chae Y. Neural substrates of acupuncture in the modulation of cravings induced by smoking-related visual cues: an fmri study. Psychopharmacology (Berl). 2013; 228 (1): Liu Z, Fang JL, Yang JS, Sun L, Wu Y, Guo L, Zhang HB, Wang YY. Immediate effects and central mechanism of acupuncture for craving of smoking based on falff: An fmri study. Chin J Tradit Chin Med Pharm. 2016; 31 (5): Gutmann LB, Sobell LC, Prevo MH, Toll BA, Gutwein CL, Sobell MB, Hyman SM. Outcome research methodology of smoking cessation trials ( ). Addict Behav. 2004; 29 (3):

18 Table 1. Participant baseline characteristics Baseline characteristics acupuncture group Auricular group NRT group Age (47.00) 44 (44.00) 40 (40.00) (40.00) 42 (42.00) 45 (45.00) Gender 61 and more 13 (13.00) 14 (14.00) 15 (15.00) Male 93 (93.00) 92 (92.00) 95 (95.00) Female 7 (7.00) 8 (8.00) 5 (5.00) Race Han 90 (90.00) 93 (93.00) 95 (95.00) Minorities 10 (10.00) 7 (7.00) 5 (5.00) Educational level Primary school and below 7 (7.00) 8 (8.00) 8 (8.00) Middle school 46 (46.00) 46 (46.00) 44 (44.00) College and above 47 (47.00) 46 (46.00) 48 (48.00) Marriage status Married 15 (15.00) 15 (15.00) 15 (15.00) Unmarried 85 (85.00) 85 (85.00) 85 (85.00) General health Poor 7 (6.00) 6 (6.00) 7 (7.00) Normal 43 (43.00) 49 (49.00) 38 (38.00) Good 50 (30.00) 45 (45.00) 55 (55.00) Alcohol consumption None 33 (33.00) 46 (46.00) 32 (32.00) Yes 67 (67.00) 54 (54.00) 68 (68.00) Smoking duration Less than 10 years 20 (20.00) 24 (24.00) 21 (21.00) years 30 (30.00) 37 (37.00) 32 (32.00) years 22 (22.00) 15 (15.00) 20 (20.00) 31 years and more 28 (28.00) 24 (24.00) 27 (27.00) Number of cigarettes smoked per day Less than 10 cigarettes 15 (15.00) 8 (8.00) 12 (12.00) cigarettes 52 (52.00) 60 (60.00) 60 (60.00) cigarettes 20 (20.00) 18 (18.00) 21 (21.00) 31 cigarettes and more 13 (13.00) 14 (14.00) 7 (7.00) Passive smoking at home Yes 9 (9.00) 13 (13.00) 9 (9.00) None 91 (91.00) 87 (87.00) 91 (91.00) Previous attempts for tobacco cessation None 47 (47.00) 52 (52.00) 50 (50.00) 1 attempt 31 (31.00) 18 (18.00) 27 (27.00) 2 and above 22 (22.00) 30 (30.00) 23 (23.00) 17

19 FTND 0-3 points 1 (1.00) 2 (2.00) 1 (1.00) 4-6 points 28 (28.00) 32 (32.00) 28 (28.00) 7 points and more 71 (71.00) 66 (66.00) 71 (71.00) Reasons to quit smoking Due to own health 84 (84.00) 80 (80.00) 86 (86.00) Due to family suggestion 35 (35.00) 28 (28.00) 35 (35.00) Due to medical suggestion 27 (27.00) 27 (27.00) 34 (34.00) Other reasons 12 (12.00) 8 (8.00) 11 (11.00) 18

20 Note: left: body acupoints selected, according to Acupuncture Point Locations in the Western Pacific Region [13] by World Health Organization; right: auricular acupoints selected, according to China National Stand Nomenclature and Location of Auricular Points (GB/T ).

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22 Note: ITT was applied; no variables were adjusted in model 1; age, sex, educational level, smoking duration, number of cigarettes smoked per day and FTND were adjusted in mode 2.

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25 e-table 1. The names and locations of study site Name of study sites Location Names of researches Institute of Acupuncture and Moxibustion, China Academy of Chinese Medical Sciences Beijing, China China-Japan Friendship Hospital Beijing, China Liu Zhao Xiyuan Hospital, China Academy of Chinese Medical Sciences Wangjing Hospital, China Academy of Chinese Medical Sciences Affiliated Hospital of Jining Medical College Haidian Hospital, Peking University Third Hospital The First Hospital of Xiamen University Jintan Hospital of Traditional Chinese Medicine Chaoyang Hospital, Capital Medical University e-figure 1. Beijing, China Beijing, China Jining, Shandong Province Beijing, China Xiamen, Fujian Province Jintan, Jiangsu Province Beijing, China Yang jin-sheng, Wang Yingying, Wu Yuan, Yang Li, Guo Lang-tao, Zhang Hao-bin Zhang Lu, Wang Ke-jian, Lu Yong-hui Chen Feng, Yuan Ying, Chen Dong-xiao Li Xiang, Yang Xian-zhang, Wang Liang Tong Shuai, Su Li, Wang Wenting Zheng Sheng-jun, Wang Yadong Yuan Hong-gui, Xing Ju-mei, Zhou wei Xiao Dan, Qin Hai-yan, Li Sheng-shu Online supplements are not copyedited prior to posting and the author(s) take full responsibility for the accuracy of all data.