Clinical efficacy of acupuncture as an adjunct to methadone treatment services for heroin addicts: a randomized controlled trial.

Am. J. Chin. Med. 2014.42:569-586. Downloaded from www.worldscientific.com by THE UNIV OF WESTERN ONTARIO on 02/01/15. For personal use only.

The American Journal of Chinese Medicine, Vol. 42, No. 3, 569–586 © 2014 World Scientific Publishing Company Institute for Advanced Research in Asian Science and Medicine DOI: 10.1142/S0192415X14500372

Clinical Efficacy of Acupuncture as an Adjunct to Methadone Treatment Services for Heroin Addicts: A Randomized Controlled Trial Yuan-Yu Chan,*,† Wan-Yu Lo,†,¶ Tsai-Chung Li,‡ Lih-Jong Shen,* Szu-Nian Yang,* Yi-Hung Chen§ and Jaung-Geng Lin‡ *Department

of Psychiatry, Taoyuan Armed Forces General Hospital, Taoyuan, Taiwan

†

Graduate Institute of Integrated Medicine ‡

School of Chinese Medicine

§ Graduate

Institute of Acupuncture Science China Medical University, Taichung, Taiwan ¶

Department of Life Science, National Chung Hsing University Taichung, Taiwan

Abstract: Scant scientific evidence supports the efficacy of acupuncture in the treatment of opiate dependence. The purpose of this study was to examine the effectiveness of acupuncture for heroin addicts on methadone maintenance by measuring the daily consumption of methadone, variations in the 36-item Short Form Health Survey-36 (SF-36) and Pittsburgh Sleep Quality Index (PSQI) scores, and heroin craving. Sixty heroin addicts were randomly assigned to true acupuncture (electroacupuncture at the Hegu [LI4] and Zusanli [ST36] acupoints, as well as acupuncture at the Ear Shenmen) or sham acupuncture (minimal acupuncture at the Hegu and Zusanli acupoints without electrical stimulation and superficial acupuncture at the Ear Shenmen), twice weekly for 4 weeks. From week 2 onwards, the daily dose of methadone was reduced by a significantly greater amount with true acupuncture compared with sham acupuncture. True acupuncture was also associated with a greater improvement in sleep latency at follow-up. All adverse events were mild in severity. Acupuncture appears to be a useful adjunct to methadone maintenance therapy (MMT) in heroin addiction.

Correspondence to: Dr. Jaung-Geng Lin, School of Chinese Medicine, China Medical University, No. 91 HsuehShih Road, Taichung 40402, Taiwan. E-mail: [email protected] or Dr. Yi-Hung Chen, Graduate Institute of Acupuncture Science, China Medical University, No. 91 Hsueh-Shih Road, Taichung 40402, Taiwan. E-mail: [email protected]

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Y.-Y. CHAN et al. Keywords: Acupuncture; Heroin Addiction; Methadone Maintenance Therapy; Clinical Trial.


Introduction Heroin addiction is a chronic medical illness and a major public health problem worldwide. The social, medical and economic problems of heroin dependence are profound and include lost productivity, disrupted relationships, crime and violence, HIV/AIDS and other infectious diseases, and death (McLellan et al., 2000; Hser et al., 2001). Methadone is widely used to curb the effects of withdrawal symptoms and block the euphoric effects of heroin. Since the advent of methadone maintenance therapy (MMT) in the mid-1960s for treating opioid addiction, long-term MMT has been the treatment of choice for heroin dependence (Dole and Nyswander, 1965, 1966a,b; American Psychiatric Association, 1994) and has proven to be an effective long-term treatment for severe opiate dependence (Ward et al., 1999). There is good evidence that MMT reduces opiate and other illicit drug use, decreases criminal activity and increases productivity (Marsch, 1998; Bloor et al., 2008). Treatment-seeking opiate users commonly cite drug-related problems with their lifestyle and health (Rounsaville and Kleber, 1985). MMT is considered to be an effective means of improving physical and mental health, social functioning (Gerstein and Lewin, 1990) and contributing to the public health goal of limiting the spread of blood-borne pathogens such as HIV, hepatitis B, hepatitis C, and others (Ward et al., 1999). Despite a strong consensus about the overall effectiveness and safety of MMT for opioid dependence, patients on MMT report a wide range of side effects, especially during the early weeks or months of methadone stabilization. The most common side effects are constipation, dizziness, drowsiness, dry mouth, headache, increased sweating, itching, lightheadedness, nausea, vomiting, and weakness. These side effects may affect adherence to MMT. High rates of co-existing psychological and psychiatric disorders have been reported amongst patients on MMT (Rounsaville et al., 1982; Darke et al., 1994). An investigation into the health status of 107 participants receiving MMT found that nearly half (44%) rated their health as fair or poor on the SF-36 and in comparison with New Zealand population norms, the study participants had significantly poorer health on all eight SF-36 scales (Deering et al., 2004). Opiate addicts often complain of sleep difficulties during MMT. Persistent insomnia among MMT patients is highly prevalent and may contribute to the risk of relapse. Prior research has reported (Stein et al., 2004; Peles et al., 2006) that up to three-quarters of MMT patients cite subjective sleep disturbance. When the Pittsburgh Sleep Quality Index (PSQI) was used to assess 322 MMT participants, over a third (40.96%) reported disrupted sleep (Kurth et al., 2009). Despite the use of MMT, opiate cravings may lead to the continued use of heroin (Fareed et al., 2011). Some studies have reported that methadone treatment may reduce heroin cravings (Ling et al., 1996; Donny et al., 2005; Eder et al., 2005; Shi et al., 2007, 2008; Barta et al., 2009), whereas other researchers have reported the opposite (Dawe and Gray, 1995; Curran et al., 1999; de Vos et al., 1999; Curran et al., 2001; Mattick et al., 2003; Ilgen et al., 2008; Walter et al., 2008). There are cases documenting patients using heroin while


ACUPUNCTURE AS AN ADJUNCT TO METHADONE TREATMENT

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participating in MMT (Hartel et al., 1995; Farre et al., 2002). Moreover, methadone is an artificial opioid compound. Long-term methadone use impairs cognitive function and sustained attention (Mintzer and Stitzer, 2002; Prosser et al., 2009) and lowers the striatal dopamine transporter function in humans (Shi et al., 2008). Therefore, adjuvant therapeutic interventions for MMT patients are needed. Acupuncture has been practiced in China since 2500 BC and is steadily gaining popularity in Western countries as an alternative and complementary therapeutic intervention (Kim et al., 2005). Acupuncture may be useful as an adjunct treatment in comprehensive management programs and might be efficacious in the treatment of pain conditions (Niu et al., 2011), such as postoperative pain (Xu et al., 2010) and cancer pain (Lin and Chen, 2012). In 1996, the World Health Organization stated that acupuncture is appropriate for the treatment of substance dependence (Culliton and Kiresuk, 1996). Major advantages regarding the use of acupuncture to treat drug addiction are that this treatment is inexpensive, simple, and lacking in side effects (Brumbaugh, 1993). Second, acupuncture may prevent opiate relapse (Cui, 1995). Third, acupuncture treatment is safe for pregnant women (Clement-Jones et al., 1979). Some basic studies have revealed that acupuncture can modify the morphine withdrawal syndrome, suppress alcohol drinking behavior (Wu et al., 1999; Yoshimoto et al., 2001) and reduce complications of drug abuse (Chen et al., 2013b). Although many studies (Bullock et al., 1987, 1989; Washburn et al., 1993; Lipton et al., 1994) have reported good efficacy with acupuncture in treating drug dependence, its effectiveness is controversial and difficult to interpret (Birch et al., 2004). The purpose of this study was to test the clinical efficacy of acupuncture as an adjunctive treatment for patients receiving outpatient MMT. This trial was randomized, shamcontrolled, and single-blind. Since all patients received methadone treatment, we expected that neither group would experience withdrawal symptoms during MMT. It was hypothesized that participants receiving true acupuncture would require less methadone during MMT and experience greater improvements in health-related outcomes, including quality of life, sleep quality and heroin craving. Materials and Methods Study Design This randomized, single-blinded, parallel-group study was designed to evaluate the clinical efficacy of acupuncture as an adjunct to MMT for heroin addicts. Major assessments were at baseline and at 4 weeks post-treatment. Clinical trial registration: ClinicalTrials.gov Identifier: NCT01512433. Subjects The study was conducted at the outpatient clinic of the Department of Psychiatry at TaoYuan Armed Forces General Hospital, a regional teaching hospital in Taiwan. Subjects were recruited from January 2012 to August 2012 through referrals from psychiatrists and

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advertisements at the clinic. Patients were included in the study only if they met the following criteria: (1) over 20 years old; (2) fulfilled the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for opiate dependence and had been receiving MMT for more than one month. Subjects were excluded if they (1) had received any antidepressant or neuroleptic medication; (2) had received any acupuncture treatment during the previous 30 days; (3) had developed severe adverse effects or had a history of events relating to acupuncture treatment; (4) had any serious physical illness; (5) had a significant risk of suicide; (6) had an infection close to the site of the selected acupoints; (7) were pregnant or were planning pregnancy; (8) had bleeding disorders or were taking anticoagulant drugs; (9) were HIVpositive. Study Procedure The study design, consent forms and procedures were approved by the Institutional Review Board of the Tri-Service General Hospital National Defense Medical Center in Taiwan. Participants showing an interest in participating in the study were initially assessed and participated in a comprehensive face-to-face interview to provide a more detailed history. All participants gave written informed consent to participate in the study before randomization. The participants completed a case report form and a set of self-reported questionnaires. Eligible participants were then randomly assigned to true acupuncture or sham acupuncture in a ratio of 1:1, with participants blinded to their assignment. Randomization was determined by a random number table generated by computer, managed by an independent administrator. At the 4-week post-treatment visits, the same assessments were repeated with all participants. The participants were informed that this study would compare different types of acupuncture. They were told that “true acupuncture” had been used in conventional Chinese medicine practice and “sham acupuncture” was a procedure that mimicked the real acupuncture procedure. It was not possible to blind the only acupuncturist in this study, due to the nature of the intervention. The analysis of the questionnaire was conducted by independent investigators blinded to each participant’s group allocation. Intervention Participants were treated twice weekly for 4 consecutive weeks. All acupuncture treatments were performed in a quiet treatment room by the same acupuncturist in the afternoon (between 12:00 PM and 06:00 PM). Treatment was administered by a qualified acupuncturist with 10 years of clinical experience with acupuncture treatment in Taiwan. The procedure involved auricular acupuncture (AA) and body electroacupuncture (EA). The participants were advised to continue MMT and methadone dosage was adjusted by an independent psychiatrist. True Acupuncture ðAA þ EAÞ Participants assigned to the true acupuncture group were given AA and body EA. The acupoints were located on the ears, hands and legs, selected on the basis of the researcher’s



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earlier systematic review on acupuncture for the treatment of opiate addiction (Lin et al., 2012) and expert opinion. Manual AA used conventional auricular stud needles consisting of a vertical needle and a horizontal circular piece of metal. The vertical needle was inserted into the ear with the horizontal circular piece of metal sitting flat on the surface of the ear. This flat circle was then covered with a small plaster. For each participant receiving manual AA, stud needles were inserted at the Ear Shenmen point in the ear cartilage ridge area for 20 min each time. The needles were removed by the therapist after treatment. EA was performed at the Hegu and Zusanli acupoints on the hands and legs with electrical stimulation via a portable electroacupuncture machine (Model HC-0601, Electronic Acupuncture Treatment Instrument, Home Care Technology Company, Taiwan). The frequency of stimulation alternated between 20 and 100 Hz (dense and disperse, DD) at automatic 2-second intervals. The intensities of the stimulations were increased in 1 mA increments to maximal tolerable intensity. The needles were left for 20 min and then removed. AA or EA stimulation typically elicits a composite of sensations termed “DeQi”, manifesting as soreness, numbness, heaviness, and distension; sensations that are believed to reflect the efficacy of the treatment. Sham Acupuncture (Placebo AA þ Minimal Acupuncture without Electrical Stimulation) Participants assigned to the sham acupuncture group were needled superficially at the same body acupoints as those used in the true acupuncture group. The superficial acupuncture was performed at the Ear Shenmen point, i.e., involving the attachment of the stud needles without vertical needle penetration, while minimal acupuncture was performed at the Hegu and Zusanli acupoints on the hands and legs. The needles were then connected to the EA machine but with no electrical stimulation. Needle penetration was to a depth of less than 4 mm to avoid “de-qi”. The acupuncturist, setting, number of points needled and duration of the treatment course were the same as those in the true acupuncture group. The subjects were told that the electric stimulator was at a fixed level and were advised to inform the acupuncturist if they felt the impulse was too strong. Efficacy Measure The primary outcome measure was change in the daily consumption of methadone and health-related quality of life. Health-related quality of life was assessed using the Taiwanese version of the SF-36 (Tseng et al., 2003), a 36-item questionnaire assessing functional health and well-being during the previous month. Testing of the Taiwanese version has demonstrated validity similar to that of other language versions (Tseng et al., 2003). It evaluates the quality of life in eight domains: physical functioning (PF), role limitations due to physical problems (RP), bodily pain (BP), general health (GH), vitality (VT), social functioning (SF), role limitations due to emotional problems (RE), and general mental health (MH) (Ware and Sherbourne, 1992). Five of the scales (PF, RP, BP, SF, and RE)


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indicate the absence of limitations or disability. The remaining three scales (GH, VT, and MH) indicate a positive state of well-being, with mid-range scores indicating no reported limitations or disabilities (McHorney et al., 1993). In this study, items in each domain were aggregated and transformed into a scale from 0 to 100, with higher scores indicating better health status (Ware et al., 1995). Secondary outcome measures were changes in sleep quality and severity of heroin craving. Sleep quality was assessed using the Taiwanese version of the PSQI (Buysse et al., 1989), which has demonstrated reliability and validity (Tsai et al., 2005). It evaluates sleep disturbances in seven subscales: subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleeping medication and daytime dysfunction. Each subscale is rated on a 4-point scale (0 to 3, with 3 indicating a more profound effect), which is summed together to yield a global score (0 to 21). Higher scores indicate greater severity of sleep disturbance and a global score > 5 indicates “poor sleep” (Buysse et al., 1989). The severity of heroin craving was assessed using a 100 millimeters visual analog scale (VAS). The amount of heroin craving that a participant feels ranges across a continuum from none to an extreme amount. The VAS score is determined by measuring in millimeters from the left hand end of the line to the point that the patient marks (Wewers and Lowe, 1990). Statistical Analysis We used SPSS version 18.0 for basic statistical analysis. Subjects who received at least 4 sessions of acupuncture were included in the statistical analysis. Baseline differences were examined using analysis of variance (ANOVA) or the 2 test. The paired t-test was used to compare treatment effects between baseline scores and post-treatment measurements. We used stepwise multiple linear regression to examine predictors of outcome. The change from baseline in daily consumption of methadone dosage to post-treatment was selected as the dependent variable, while demographics, treatment group, baseline SF-36 score, baseline total PSQI score and baseline craving score were chosen as possible predictors. Change in methadone dosage was selected as the dependent variable because it is the only objective outcome measure in this study.

Results Study Population Of 175 adults assessed for eligibility, 85 were deemed ineligible (either failing to meet inclusion criteria [n ¼ 42] or reportedly disinterested [n ¼ 43]). Sixty participants were randomly assigned to true acupuncture or sham acupuncture (Fig. 1). Table 1 summarizes the demographics and baseline clinical characteristics, which were well balanced between the groups. Participants had a mean age of 36.15 years and 49 (81.7%) participants were male. Most had never married (36.7%), were employed (73.3%), and had a high school level


575

Assessed for eligibility (n=175)

Excluded (n=85) Not meeting inclusion criteria (n=42) Declined to participate (n=43)


Randomized (n=60)

Allocated to true acupuncture group (n=30)

Allocated to sham acupuncture group (n=30)

Completed (n=29) Withdrawal (n=1) [imprisonment])

Completed (n=29) Withdrawal (n=1) [imprisonment])

Analyzed (n=30)

Analyzed (n=30) Figure 1. Participant flowchart.

of education (60.0%). Heroin and amphetamine abuse histories averaged 7.05 and 5.08 years, respectively. The daily consumption of methadone was 53.01 mg. SF-36 and PSQI outcome measures did not differ significantly between the two groups. Two subjects (3%) (1 from each group) dropped out during week 4 after study entry. The reasons given for both were imprisonment. Dropout rates did not differ significantly between the groups. Daily Consumption of Methadone In the true acupuncture group, there was a significant decrease in the daily consumption of methadone dosage during weeks 2–4 and at post-treatment: decreases of 3.66 mg/day at week 2, 7.70 mg/day at week 3, 9.95 mg/day at week 4 and 8.10 mg/day at post-treatment. In contrast, no significant difference in the daily consumption of methadone dosage from baseline to post-treatment occurred with sham acupuncture. The reductions in methadone dosage differed significantly between the groups from week 2 to post-treatment (Table 2). Stepwise multiple regression revealed that the treatment group (β ¼ 8:55, p ¼ 0:002), amphetamine abuse history (β ¼ 0:6, p ¼ 0:012) and baseline methadone dosage (β ¼ 0:115, p ¼ 0:043) were significant predictors of the change in methadone dosage from baseline to post-treatment. Participants with a high baseline methadone dosage randomized to true acupuncture had a greater decrease in methadone dosage than their counterparts

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Y.-Y. CHAN et al. Table 1. Demographic and Clinical Characteristics of the Participants


Variable Definition Age (years) Sex (male/female) Marital status Never married Married/cohabiting Divorced/widowed Occupation Employed Unemployed Education (years) 12–15 15–18 18–22 Heroin use (years) Amphetamine use (years) Heroin urine screen Positive Negative SF-36 PF RP RE VT MH SF BP GH Methadone dosage (mg) PSQI Subjective sleep quality Sleep latency Sleep duration Habitual sleep efficiency Sleep disturbance Use of sleep medications Daytime dysfunction Total scores Heroin craving score (mm)

True Acupuncture Sham Acupuncture (n ¼ 30) (n ¼ 30)

Total (n ¼ 60)

37.00 7.25 26/4

35.30 6.66 23/7

36.15 6.96 49/11

12 (40.0) 7 (23.3) 11 (36.7)

9 (30.0) 15 (50.0) 6 (20.0)

21 (35.0) 22 (26.7) 17 (28.3)

21 (70.0) 9 (30.0)

23 (76.7) 7 (23.3)

44 (73.3) 16 (26.7)

9 (30.0) 20 (66.7) 1 (3.3) 6.53 4.44 5.05 6.12

14 (46.7) 16 (53.5) 0 (0.0) 7.57 5.03 5.12 5.79

23 (38.3) 36 (60.0) 1 (1.7) 7.05 4.73 5.08 5.91

8 (26.7) 15 (50.0)

8 (26.7) 15 (50.0)

16 (26.7) 30 (50.0)

19.28 42.51 43.71 18.05 15.57 19.12 21.34 21.72 26.22

1.70 0.88 1.93 0.91 1.33 1.27 1.27 1.23 1.67 0.66 0.97 1.25 1.33 0.96 10.20 4.22 44.67 34.61

76.67 54.17 36.67 49.83 50.40 65.00 74.92 46.17 54.46

22.18 43.09 42.30 17.74 18.95 26.34 24.79 19.99 23.10

2.07 0.69 1.77 1.00 1.70 1.26 1.63 1.27 1.50 0.68 1.63 1.35 1.73 0.98 12.03 3.94 50.67 33.31

78.00 51.67 42.22 46.33 53.87 63.33 64.92 43.00 51.56

2 = t Value a p-Value 0.946 1.002 4.808

0.348 0.317 0.090

0.341

0.559

2.531

0.282

0.844 0.043 0.000

0.402 0.966 1.000

77.33 20.61 52.92 42.46 39.44 4.74 48.08 17.83 52.13 17.29 64.17 22.84 69.92 23.48 44.58 20.75 53.01 24.54

0.248 0.226 0.500 0.758 0.774 0.280 1.675 0.588 0.453

0.805 0.822 0.619 0.452 0.442 0.780 0.099 0.559 0.652

1.88 0.80 1.85 0.95 1.52 1.27 1.45 1.25 1.58 0.67 1.30 1.33 1.53 0.98 11.12 4.15 47.67 33.82

1.798 0.674 1.122 1.135 0.961 1.987 1.598 1.738 0.684

0.077 0.503 0.267 0.261 0.0341 0.052 0.116 0.087 0.497

Note: Data are presented as mean SD or number (%). SF-36 ¼ Short Form Health Survey-36; PF ¼ physical functioning; RP ¼ role limitations due to physical problems; BP ¼ bodily pain; GH ¼ general health; VT ¼ vitality; SF ¼ social functioning; RE ¼ role limitations due to emotional problems; MH ¼ general mental health; PSQI ¼ Pittsburgh Sleep Quality Index. a Comparison between true acupuncture and sham acupuncture by 2 or unpaired t-test.


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Table 2. Daily Consumption and Decreased Dosage of Methadone True Acupuncture

Sham Acupuncture


Mean (SD) Paired t-Test Mean (SD) Paired t-Test ANOVA p-Value p-Value p-Value Baseline (mg/day) Week 1 (mg/day) Week 2 (mg/day) Week 3 (mg/day) Week 4 (mg/day) Post-Treatment (mg/day)

Week 1-Baseline (mg/day) Week 2-Baseline (mg/day) Week 3-Baseline (mg/day) Week 4-Baseline (mg/day) Post-TreatmentBaseline (mg/day)

54.46 53.53 50.79 46.76 44.50 45.86

(23.10) (22.86) (23.31) (23.40) (24.20) (24.55)

0.122 0.002 0.000 0.000 0.003

51.56 50.05 51.60 52.86 52.22 52.13

(26.22) (27.48) (25.82) (26.06) (25.86) (25.61)

0.125 0.963 0.428 0.679 0.695

0.596 0.899 0.344 0.238 0.346 p-Value Mean Difference (95% CI)

Mean (SD)

Mean (SD)

0.92 (3.17)

1.51 (5.25)

0.600

(1.65, 2.83)

3.66 (6.06)

0.04 (4.31)

0.008

(6.42, 0.98)

7.70 (8.89)

1.29 (8.81)

0.000

(13.57, 4.42)

9.95 (11.97)

0.65 (8.57)

0.000

(15.99, 5.23)

8.10 (13.37)

0.57(7.86)

0.004

(14.39, 2.94)

randomized to sham acupuncture. A higher amphetamine abuse history was associated with greater methadone consumption. Health-Related Quality of Life Table 3 summarizes SF-36 results at baseline and post-treatment in both groups. RE and GH scale scores were significantly improved from baseline with true acupuncture, while BP scores were significantly improved with sham acupuncture. SF-36 subscale scores did not differ significantly between the groups. Sleep Quality Table 4 presents the mean values for secondary outcomes by treatment condition at baseline and post-treatment. Post-treatment PSQI scores in the true acupuncture group were significantly improved from baseline for subjective sleep quality, sleep latency, daytime dysfunction and total scores. The total PSQI score was reduced from 12.03 to 9.00 in the true acupuncture group. No such improvements in PSQI subscale scores occurred in the sham acupuncture group. The only significant between group difference was for sleep latency, with subjects in the true acupuncture group showing greater improvement than those in the sham acupuncture group.

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Y.-Y. CHAN et al. Table 3. SF-36 Results at Baseline and Post-Treatment


True Acupuncture

SF-36 PF Baseline Post-Treatment RP Baseline Post-Treatment RE Baseline Post-Treatment VT Baseline Post-Treatment MH Baseline Post-Treatment SF Baseline Post-Treatment BP Baseline Post-Treatment GH Baseline Post-Treatment

Sham Acupuncture

ANOVA Paired t-Test p-Value p-Value

Mean (SD)

Paired t-Test p-Value

Mean (SD)

76.67 (22.18) 76.00 (27.77)

0.908

78.00 (19.28) 75.17 (27.18)

0.409

0.907

54.17 (43.09) 64.17 (39.76)

0.259

51.67 (42.51) 56.67 (43.52)

0.579

0.489

36.67 (42.30) 62.22 (40.81)

0.003

42.22 (43.71) 50.00 (46.94)

0.457

0.286

49.83 (17.74) 53.33 (23.39)

0.400

46.33 (18.05) 46.17 (21.20)

0.962

0.219

50.40 (18.95) 55.60 (23.89)

0.259

53.87 (15.57) 53.87 (19.02)

1.000

0.757

65.00 (26.34) 69.58 (23.60)

0.420

63.33 (19.12) 65.42 (24.50)

0.550

0.505

74.92 (24.79) 80.17 (23.36)

0.284

64.92 (21.34) 74.33 (22.20)

0.022

0.326

46.17 (19.99) 54.83 (22.38)

0.012

43.00 (21.72) 47.67 (21.92)

0.167

0.215

Note: PF ¼ physical functioning; RP ¼ role limitations due to physical problems; BP ¼ bodily pain; GH ¼ general health; VT ¼ vitality; SF ¼ social functioning; RE ¼ role limitations due to emotional problems; MH ¼ general mental health.

Heroin Craving Scores for heroin craving were significantly improved in both treatment groups, with a reduction from 50.67 to 14.14 in the true acupuncture group. However, post-treatment heroin craving scores did not differ significantly between the groups (Table 5).

Adverse Events Both forms of acupuncture were well tolerated. Two subjects in the true acupuncture group reported slight bleeding at the site of acupuncture, and one additional subject reported mild hand numbness. In the sham acupuncture group, only one subject reported slight bleeding at the site of acupuncture. All adverse events were mild in severity.


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Table 4. PSQI Results at Baseline and at 4 Weeks Post-Treatment True Acupuncture

Sham Acupuncture


ANOVA Mean (SD) Paired t-Test p-Value Mean (SD) Paired t-Test p-Value p-Value PSQI Subjective Sleep Quality Baseline Post-Treatment Sleep Latency Baseline Post-Treatment Sleep Duration Baseline Post-Treatment Habitual Sleep Efficiency Baseline Post-Treatment Sleep Disturbance Baseline Post-Treatment Use of Sleep Meds Baseline Post-Treatment Daytime Dysfunction Baseline Post-Treatment Total Scores Baseline Post-Treatment

2.07 (0.69) 1.34 (0.90)

0.000

1.70 (0.88) 1.45 (0.87)

0.165

0.657

1.77 (1.00) 1.21 (0.98)

0.003

1.93 (0.91) 1.76 (0.99)

0.424

0.037

1.70 (1.26) 1.41 (1.12)

0.212

1.33 (1.27) 1.41 (1.24)

0.876

1.000

1.63 (1.27) 1.38 (1.37)

0.495

1.27 (1.23) 1.55 (1.21)

0.282

0.614

1.50 (0.68) 1.28 (0.65)

0.136

1.67 (0.66) 1.59 (0.57)

0.602

0.058

1.63 (1.35) 1.28 (1.33)

0.119

0.97 (1.25) 1.00 (1.28)

0.769

0.425

1.73 (0.98) 1.10 (0.90)

0.006

1.33 (0.96) 1.07 (0.80)

0.161

0.878

12.03 (3.94) 9.00 (4.80)

0.002

10.20 (4.22) 9.83 (4.17)

0.664

0.486

Table 5. Heroin Craving Results at Baseline and at 4 Weeks Post-Treatment True Acupuncture

Sham Acupuncture

ANOVA Mean (SD) Paired t-Test p-Value Mean (SD) Paired t-Test p-Value p-Value Heroin Craving Score Baseline 50.67 (33.31) Post-Treatment 14.14 (22.12)

0.000

44.67 (34.61) 24.83 (26.54)

0.002

0.101

Discussion To the best of our knowledge, this study is the first of its kind to investigate the clinical efficacy of EA combined with AA for MMT patients. The results of this study, as measured by the daily consumption of methadone, scores on the SF-36 and PSQI, and level of heroin craving, suggest that ear acupuncture combined with body EA may contribute to improved


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outcomes in opiate-dependent patients when administered as an adjunctive treatment to MMT. Our rationale for choosing the Zusanli (ST36), Hegu (LI4) and Shenmen (ear) acupoints for treatment of opiate addiction is based on our earlier systematic review (Lin et al., 2012). That review identified seven studies (Washburn et al., 1993; Zhang et al., 2000; Montazeri et al., 2002; Wu et al., 2003; Mu et al., 2005; Wen et al., 2005; Zeng et al., 2005) providing positive evidence for acupuncture in the treatment of opiate addiction, which included EA, manual acupuncture, Han’s acupoint nerve stimulator and auricular acupuncture (AA); three further studies (Wells et al., 1995; Margolin et al., 2005; Bearn et al., 2009) reported no efficacy with AA in the treatment of opiate addiction. The most frequently used points on the extremities and ear for the treatment of opiate addiction consist of the Zusanli (ST36), Sanyinjiao (SP36), Hegu (LI4), Neiguan (PC6), Shenmen (ear), Sympathetic (ear), Kidney (ear) and Lung (ear). Zusanli (ST36) and Hegu (LI4) are major acupoints for acupuncture analgesia (Claunch et al., 2012). Hegu (LI4) has a pain relief function in the head, neck and large intestine, while Zusanli (ST36) is frequently used for the relief of gastrointestinal tract pain. It has been proposed that their effects are associated with releasing opioid neuropeptides, which interact with -, - and -opioid receptors (Wang et al., 2008; Han, 2011) and may possibly help to reduce heroin dependence symptoms. In addition, EA at Zusanli (ST36) is effective for improving gastric motility and relieving constipation symptoms (Chen et al., 2013a). Acupuncture at the Shenmen (ear) is effective in treating insomnia (Cao et al., 2009), increasing oxygen uptake, decreasing heart rate and blood lactic acid (Lin et al., 2011). We therefore chose acupuncture at the Hegu (LI4), Zusanli (ST36) and Shenmen (ear) points as an adjunct to methadone treatment services for treating heroin dependence, pain, insomnia and constipation symptoms. This study was not designed to test the mechanism of action of acupuncture. The bestknown mechanism is via endogenous opiates and their receptors, relieving painful conditions, aiding drug withdrawal, and producing other physiological effects (Han, 2004). Low-frequency EA (2 Hz) accelerates the release of β-endorphin, endomorphin and encephalin, all of which interact with - and -opioid receptors, whereas high-frequency EA (100 Hz) accelerates the release of dynorphin, which interacts with -opioid receptors (Han et al., 1986, 1991; Han, 2003, 2004). Previous research has shown increases in the release of the neuropeptide substance P per pulse of electrical stimulation using frequencies in the range of 20–50 Hz (Racke et al., 1989), with maximal effect at 20 Hz (Go and Yaksh, 1987). This study used stimulation alternating between 20 and 100 Hz to produce the simultaneous release of all four opioid neuropeptides. Previous research has reported that acupuncture affects the reinforcing effects of morphine. Wang et al. reported that morphine-induced place preference in rats is significantly suppressed by 2 Hz EA (Wang et al., 2000). However, Shi et al. showed that 100 Hz EA significantly attenuated morphineinduced conditioned place preference, and this effect was completely blocked by - and -opioid receptor antagonists, suggesting that the anti-craving effects induced by 100 Hz EA are mediated by the activation of - and -opioid receptors (Shi et al., 2003). Some studies have reported that EA and AA produce beneficial effects on sleep quality in patients with insomnia, which may be associated with repairing sleep architecture,



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reconstructing sleep continuity, as well as prolonging slow wave sleep time and rapid eye movement (REM) sleep time (Cao et al., 2009; Ruan et al., 2009; Yeung et al., 2009a,b). Another study has suggested that EA could be a potential treatment for sleep disturbance during morphine withdrawal by producing a significant increase in REM sleep, non-REM sleep and total sleep time (Li et al., 2011). Thus, the activation of the endogenous opioid system by acupuncture may help to reduce heroin craving and improve sleep quality, but further research is needed to further delineate the mechanisms of action. We found that with the true acupuncture adjunct to MMT, the required dose of methadone was significantly lower than at baseline. Methadone is neurotoxic because it is a long-acting synthetic opioid drug. Wang et al. showed that methadone dose was highly related to the degree of white matter injury and impaired brain white matter integrity in long-term MMT patients (Wang et al., 2011). Thus, we hypothesize that this reduction in the required dose of methadone might attenuate possible neuronal damage in MMT patients. By the end of this study, participants who received true acupuncture reported that the daily consumption of methadone dosage was decreased by 8.10 mg/day, the SF-36 GH subscale scores were improved by an average of 8.6 points, total PSQI scores by 3.0 points and heroin craving scores had decreased by 36.5 points. However, the mean PSQI score of 9.0 at posttreatment was considerably higher than the cut-off of 5 reflecting normal sleep, indicating that subjects were still suffering from insomnia despite true acupuncture treatment. This study has several limitations. First, subjects were recruited through our methadone replacement therapy outpatient department and agreed to participate in this study, which could suggest that these subjects had high expectations in the effectiveness of acupuncture, thereby over-optimizing the clinical responses in both the true and sham acupuncture groups. This may affect the subjective evaluation of intra-group results. Second, all participants received MMT, which may have masked some of the effects of acupuncture. Third, the duration of treatment was four weeks, and the results may not generalize to other acupuncture treatment protocols of shorter durations. We hypothesized that increasing treatment frequency, duration and having individually tailored acupuncture regimens would improve efficacy. Larger controlled studies with long-term treatment protocols and follow-up periods are necessary to replicate these results. Despite these limitations, this study has a number of noteworthy strengths. It was a single blind, sham-controlled, randomized clinical trial. The same acupoints were used in both acupuncture groups, with treatment differing only in the level of stimulation. Finally, the findings demonstrate some advantage of true acupuncture over sham acupuncture as an adjunct to MMT. In terms of safety and treatment compliance, the 4-week twice-weekly course of true acupuncture and sham acupuncture was well tolerated and accepted by most participants. Conclusion Scant evidence supports the use of acupuncture for the treatment of opiate dependence. The results of this study suggest that acupuncture can be considered as a safe, well tolerated, and potentially useful non-pharmacologic intervention for opiate dependence.

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Acknowledgments This work was supported by grant NSC 100-2320-B-039-029-MY2 from the National Science Council, Taipei, Taiwan.


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