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. 2008 Dec 25;29(4):449–454. doi: 10.1007/s10571-008-9336-4

A Meta-Analysis of Acupuncture Combined with Opioid Receptor Agonists for Treatment of Opiate-Withdrawal Symptoms

Ting-ting Liu 1, Jie Shi 1,✉, David H Epstein 2, Yan-ping Bao 1, Lin Lu 1,✉
PMCID: PMC3689320  NIHMSID: NIHMS481519  PMID: 19109766

Abstract

This review extends a prior meta-analysis of acupuncture’s utility for treating opioid detoxification, addressing the efficacy of acupuncture when combined with allopathic therapies. Both English and Chinese databases were searched for randomized trials comparing acupuncture combined with opioid agonist treatment versus opioid agonists alone for treating symptoms of opioid withdrawal. The methodological quality of each study was assessed with Jadad’s scale (1–2 = low; 3–5 = high). Meta-analysis was performed with fixed- or random-effect models in RevMan software; the outcome measures assessed were withdrawal-symptoms score, relapse rate, side effects, and medication dosage. Withdrawal-symptom scores were lower in combined treatment trials than in agonist-alone trials on withdrawal days 1, 7, 9, and 10. Combined treatment also produced lower reported rates of side effects and appeared to lower the required dose of opioid agonist. There was no significant difference on relapse rate after 6 months. This meta-analysis suggests that acupuncture combined with opioid agonists can effectively be used to manage the withdrawal symptoms. One limitation of this meta-analysis is the poor quality of the methodology of some included trials. High-quality studies are needed to confirm findings regarding the side effects and medication dosage.

Keywords: Acupuncture, Opioid, Detoxification, Meta-analysis

Introduction

Acupuncture is a traditional Chinese medical treatment developed over 2,000 years ago, in which needles are inserted into the skin to stimulate specific points. Related, needle-free techniques provide stimulation through manual application of pressure (acupressure), electrical charge, or a laser beam (Linde et al. 2001). For at least the past 30 years, acupuncture has been used internationally to treat drug-abuse and dependence (Wen and Teo 1975; Wen 1977). For instance, auricular acupuncture treatment is available at over 400 substance-abuse clinics in the United States and Europe.

However, acupuncture’s efficacy as a drug-abuse treatment has been the subject of conflicting findings in clinical trials; some findings have been promising (Margolin et al. 2002), but others showed no difference between auricular and sham acupuncture (Avants et al. 2000). A recent systematic review has indicated that there is no evidence for the effectiveness of auricular acupuncture in treating cocaine dependence (Gates et al. 2006). We know of no published systematic review of acupuncture’s effectiveness in treating opioid dependence, possibly because most of the encouraging results have come from nonrandomized trials (Ter Riet et al. 1990; Linde et al. 2001; Jordan 2006).

However, Chinese researchers have begun studying acupuncture as an adjuvant treatment—augmenting rather than replacing allopathic medications during opioid detoxification. Some studies have indicated that acupuncture, in this ancillary role, can significantly decrease the dosage of buprenorphine or methadone needed to allay the withdrawal symptoms. Further, some of these studies suggest that the combined treatment may lead to lower relapse rates (Wu et al. 1999, 2001). These studies have not been widely cited, partly because most have been published in Chinese journals. To remedy this situation, Min (2007) published a review of relevant trials completed through 2005 and argued that both acupuncture alone and acupuncture combined with medication were more effective than medication alone in relieving heroin-withdrawal symptoms. In that review, both randomized controlled trials and quasi-randomized controlled trials were included, and trials were included without regard to medications co-administered in combined treatments. These factors may have affected the conclusions.

Here, using meta-analytic techniques, we replicate and extend Min’s systematic review, focusing exclusively on the effectiveness and safety of acupuncture as an adjuvant treatment during opioid detoxification.

Methods

Literature Search

After a preparatory literature search, we found that the studies in which acupuncture was used as an adjuvant treatment had usually been carried out in China. No RCTs meeting our criteria were found in English language journals. The relevant body of research in China began in the early 1990s. Therefore, the time span of our final literature search was January 1990 to February 2008. To locate all the reports of relevant clinical trials, we searched English language databases (EMBASE, PUBMED, and the Cochrane Central Register of Controlled Trials) as well as Chinese databases (Chinese Biomedical Literatures, China National Knowledge Infrastructure, Wanfang, and VIP). Our search strategy was to focus on the keywords “heroin” and “acupuncture,” also searching for their synonyms and closely related words such as “opioid, opiate, morphine,” “acupressure, auricular acupuncture, electroacupuncture, ear acupuncture, needle,” and “detoxification, dependence, withdrawal,” and for combinations of these words. We searched for the Chinese counterparts of these words in the Chinese databases. We identified relevant reports by reading the titles and abstracts of the search results. We also inspected the reference list from each relevant article. Finally, we contacted experts in the field to gather information on the ongoing and unpublished studies.

Inclusion and Exclusion Criteria

We included studies that met the following criteria: (1) randomized controlled trial focusing on opioid detoxification, using a double-blind, single-blind, and nonblind design; (2) participants met criteria for opioid–heroin dependence (by DSM-IIIR, or DSM-IV criteria, with opioid-abuse history, documented abstinence syndrome, and positive urine test), and were in the acute stage of the abstinence syndrome (lachrymation, yawning, sweating, diarrhea, insomnia, fatigue, etc.); (3) the trial compared an experimental group receiving acupuncture combined with opioid receptor agonists (AT plus ORA) versus a control group receiving any opioid receptor agonists (ORA) or partial opioid receptor agonists (pORA); (4) the trial included at least one of the following outcome measures: total score for opioid-withdrawal symptoms, relapse rate, side effects, or medicine dosage needed to allay withdrawal; and (5) there were at least 15 participants in each group.

Exclusion criteria included: (1) nonnumeric data and (2) re-publication.

Data Extraction and Quality Assessment

Two reviewers read the titles and abstracts of search hits to assess each article suitability for inclusion. Uncertainties were resolved through discussion. The following key information was extracted from each study: first author, publication year, study design, sample size, patients’ demographic characteristics and drug-use history, detailed description of the intervention, and their outcomes.

The methodological quality of the included trials was assessed using the Jadad scale (Jadad et al. 1996), which rates studies for: (1) randomization, (2) double-blinding, (3) description of withdrawal, (4) description of randomization, and (5) description of blinding. Trials scoring 1 or 2 points are considered low-quality, while trials scoring 3–5 points are considered as high-quality.

Data Synthesis and Analysis

Demographic information for all participants in the included studies was summarized and analyzed using RevMan software (Cochrane Collaboration 2004). Continuous outcomes (such as scores on rating scales) were assessed in terms of the weighed mean difference (WMD) between two groups. Dichotomous outcomes (such as relapse rate) were assessed in terms of relative risk (RR). For both types of outcome, 95% confidence intervals (CIs) were calculated. Random-effect models were used to analyze pooled effects when heterogeneity was significant; otherwise, fixed-effect models were used. Differences were taken to be statistically significant when 95% CIs did not overlap (a more stringent criterion than a significance test at P < 0.05) (Wolfe and Hanley 2002). Fail-safe numbers were assessed to estimate the number of unpublished negative studies that would be needed to offset the observed results (Rosenthal 1979).

Results

Characteristics of Studies

We identified 21 reports of RCTs of acupuncture therapy combined with opioid receptor agonists for heroin detoxification; of these studies, 11 (with a total of 1,105 participants) were eligible for inclusion in the meta-analysis (see Table 1 for study details). The average age of participants in the included studies ranged from 24.0 to 34.2 years, and most participants were males (82.0%). The drug abused in these studies was heroin, with no mention of other classes of drugs. The average amount of daily heroin use was 0.45–1.80 g, with an average duration of use for 38.9–98.4 months. Intravenous injection and insufflation were the most commonly reported routes of administration in the included studies. The most commonly used specific acupoints were neiguan, zusanli, shenmen, hegu, and sanyinjiao (Jin 2007). The average duration of needling or electrical stimulation time was 20–50 min, with a frequency of once or twice per day. All of the included trials scored 2 points on the Jadad scale and were thus characterized as low-quality studies. The two points were for randomization and description of withdrawal. The included trials received no points for details of randomization or for double-blind design.

Table 1.

Characteristics of included studies

Author and Year Jadad score Participants Intervention Duration (days) Outcomes
N AT + ORA/ORA AT + ORA ORA AT + ORA/ORA
Age-year Male% Age-year Male%
(He and Li 2005a) 2 70/70 24.00 – 23.00 – AT + methadone/methadone 15 2;3
(He and Li 2005b) 2 35/35 28.12 85.71 28.30 82.86 AT + methadone/methadone 15 1;3
(Li et al. 2004) 2 40/40 30.16 77.50 28.45 82.50 AT + buprenorphine/buprenorphine 10 1;4
(Liu et al. 2005a) 2 74/74 28.25 91.89 27.20 89.19 AT + methadone/methadone 10 1;4
(Rong et al. 2005) 2 33/31/30 31.80/31.90 84.85/87.10 29.20 83.33 Scalp AT + methadone/body AT+methadone/methadone 10 1
(Wang et al. 1999a) 2 60/60 – – – – AT + methadone/methadone 10 2;3
(Wang et al. 1999b) 2 100/100 – 86.00 – 87.00 AT + methadone/methadone 10 2;3
(Wang et al. 2005) 2 60/60 – 81.67 – 85.00 AT + methadone/methadone 10 2;3
(Wu et al. 2003) 2 30/30 – – – – AT + opiate/opiate + buprenorphine 10 1;4
(Zeng et al. 2004) 2 31/26 33.16 83.87 34.23 80.77 AT + methadone/methadone 10 1
(Zhang et al. 2004) 2 43/43 26.52 85.00 28.11 93.02 AT+methadone/methadone 10 1;4
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Note: 1: total score of WSS; 2: relapse rate; 3: number of patients detoxified; 4: frequency of side effects

Efficacy of Combined Treatment (AT plus ORA)

Total Withdrawal Symptom Score (WSS)

Seven trials assessed the severity of withdrawal symptoms using the withdrawal symptom scale (Himmeisbach and Andrews 1943). We analyzed the combined data from these studies (Fig. 1). Pretreatment baseline scores (D0) were similar across the treatments. For the first (D1), seventh (D7), and the final 2 days (D9, D10), combined treatment was significantly more effective than the agonist treatment alone. The WMDs and 95% CIs were: D1, 3.67 [−5.83, −1.52]; D7, 9.54 [−17.99, −1.09]; D9, 9.50 [−16.15, −2.84]; D10, 7.51 [−11.80, −3.22]. There were no significant differences between the groups at other time points, but when nonsignificant differences were apparent, they favored combined treatment.

Fig. 1.

Fig. 1

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Efficacy of acupuncture therapy plus opioid receptor agonists (AT ± ORA) versus ORA in alleviating opioid withdrawal symptoms. Summary estimates of the weighed mean differences (WMDs) and their 95% CIs are given day by day. D0 indicates pretreatment baseline. D0 and D1 were analyzed with fixed-effect models. The other time points were analyzed with random-effect models. N R indicates the failsafe number, i.e., the number of unpublished negative studies that would be required to negate each significant finding at an alpha level of 0.05

Relapse Rate

Four trials, involving a total of 524 participants, included 6-month follow-up evaluations to assess relapse rate after discontinuation of acupuncture. The 6-month relapse rates in combined groups and control groups were: 87% vs. 97% (He and Li 2005a); 26.6% vs. 56.8% (Wang et al. 1999a); 29.0% vs. 59.5% (Wang et al. 1999b); and 28.3% vs. 47.8% (Wang et al. 2005). Pooled analysis showed no significant effect of acupuncture (Fig. 2). The RR and 95% CI were 0.60 [0.32, 1.10], P = 0.10.

Fig. 2.

Fig. 2

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Efficacy of acupuncture therapy plus opioid receptor agonists (AT ± ORA) versus ORA in reducing rate of relapse at 6 months. Summary estimates of the relative risk (RR) and its 95% CI were analyzed with random-effect models

Safety of Combined Treatment (AT plus ORA): Side Effects

Insufficient data were available to perform pooled analysis on side-effect incidence; only four trials mentioned side effects during the treatment. The most common side effects reported were nausea, vomiting, dry mouth, blurred vision, and headache. While one study showed no significant differences in side effects between the groups (Wu et al. 2003), another found that the incidence of side effects was significantly less in the AT + ORA group than in the ORA group (Li et al. 2004). The two other studies found that the most common complaint in AT + ORA recipients was muscle twitching from electroacupuncture, which was well tolerated after explanation and intensity adjustment (Zhang et al. 2004; Liu et al. 2005a).

Other Comparison: Medicine Dosage Used

In three of the included trials, the investigators attempted to reduce the dose of opioid agonist for the AT + ORA group (using half the dose given to the ORA group) (Li et al. 2004, 2005a; Zhang et al. 2004) and withdrawal syndromes were managed smoothly in both the groups. In the other eight trials, the doses were equal across the groups. The dosage of opioid agonist was determined in accordance with the amount of heroin abused, and decreased gradually across 10 or 15 days. The starting doses were less than 60 mg/day for methadone, 0.8–1.6 mg/day for buprenorphine, and 300 mg/day for morphine.

File-Drawer Effect

To address the “file-drawer problem” (the possibility that unpublished negative findings would negate the findings of the published studies), we calculated the fail-safe number N R (Rosenthal 1979), representing the number of studies with null results that would render each of our findings nonsignificant at P = 0.05. N Rs are shown in the right-hand column of Fig. 1. Note that N R is calculated in terms of significant differences at P = 0.05, which sometimes emerge even in instances when 95% CIs overlap (Wolfe and Hanley 2002).

Discussion

Our meta-analysis revealed that individuals receiving acupuncture therapy combined with opioid agonist treatment showed lower scores for opioid-withdrawal symptoms than individuals receiving only opioid agonists, on the first day and three of the last days of a 10-day taper. There was no significant difference between the two groups in terms of relapse rate at 6 months.

Our present findings differed somewhat from those of the earlier meta-analysis that we sought to replicate and extend (Min 2007). That study concluded that acupuncture combined with medication was more efficacious than medication alone from days 1 to 10, and that subsequent relapse rates were lower after the combination treatment. This difference may be due to different inclusion criteria between the two meta-analyses; unlike Min (2007), we included only RCTs and restricted the control group treatment to opioid agonists.

Theoretically, acupuncture as applied by qualified practitioners in the traditional way should have no side effects (Lu et al. 2004; Min 2007). The side effects that were reported in a few of the included trials seem to have resulted from improper application of electrical impulses in electroacupuncture, and these side effects were remedied by adjustment of the electroacupuncture intensity. In the included trials, acupuncture not only rarely caused side effects but also diminished the side effects caused by the opioid agonists. One included trial showed that its combined-therapy group had fewer side effects than the group receiving agonist medication alone (Li et al. 2004). Also, in three included trials, doses of opioid agonists half those used in the medication alone groups were used in conjunction with acupuncture, and combined group participants’ withdrawal syndromes were managed effectively. Because acupuncture is inexpensive, simple, and essentially free of side effects, further research on its application as a complementary therapy should be performed to facilitate dosage reduction of conventional medicine.

The styles of acupuncture in the meta-analyzed trials included traditional needle puncturing, auricular acupuncture, and electroacupuncture. According to the theory of acupuncture, bodily functions are controlled by systems of “Jingluo” and “Qi-xue,” and pressure applied through needles improves the functioning of these systems (Shi et al. 2006). In rats, acupuncture at acupoint HT7 significantly decreases both dopamine release in the nucleus accumbens and behavioral hyperactivity induced by a systemic morphine challenge (Kim et al. 2005). Peripheral electric stimulation in rats inhibits morphine-induced place preference (Wang et al. 2000) and attenuates the signs of morphine withdrawal (Liu et al. 2005b). Some of the effects of electroacupuncture may be mediated by release of endogenous peptides such as enkephalins and dynorphin (Han et al. 1991; Chen and Han 1992).

The existing evidence indicates that acupuncture combined with an opioid agonist is efficacious for treatment of opioid withdrawal and may have the potential to decrease the agonist dosage needed and alleviate the side effects of the agonist. However, there is no strong evidence that the combination is otherwise superior to treatment with an opioid-agonist alone, and the question is still open. A major limitation of this meta-analysis is the poor methodological quality of the included trials. Unfortunately, none of the included trials used a double-blind design: the control groups did not receive sham acupuncture. The published results also lacked adequate details about randomization. Also, because all the included trials were conducted in China, their results may not be generalizable to other regions. Thus, high-quality research is essential for more definitive conclusions.

Acknowledgments

This work was supported in part by the National Basic Research Program of China (973 Program, 2003CB515400), the National High Technology Research and Development Program of China (863 Program, 2006AA02Z4D1), and the China-Canada Joint Health Research Program (No: 30611120528).

Contributor Information

Jie Shi, FAX: +86-10-62032624, Email: shijie@bjmu.edu.cn.

Lin Lu, Email: linlu@bjmu.edu.cn.

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