Acupuncture for the Treatment of Opiate Addiction

Acupuncture is an accepted treatment worldwide for various clinical conditions, and the effects of acupuncture on opiate addiction have been investigated in many clinical trials. The present review systematically analyzed data from randomized clinical trials published in Chinese and English since 1970. We found that the majority agreed on the efficacy of acupuncture as a strategy for the treatment of opiate addiction. However, some of the methods in several included trials have been criticized for their poor quality. This review summarizes the quality of the study design, the types of acupuncture applied, the commonly selected acupoints or sites of the body, the effectiveness of the treatment, and the possible mechanism underlying the effectiveness of acupuncture in these trials.


Introduction
Acupuncture, the practice of inserting thin solid needles into specific documented points of the body to treat many different disorders, has been practiced in China since 2500 BC [1]. Acupuncture is gaining popularity in Western countries as an alternative and complementary therapeutic intervention, and this therapeutic technique is also growing in popularity worldwide [2,3]. Acupuncture is based on the principles of traditional oriental medicine and was developed according to the principle that human bodily functions are controlled by the "meridian" and "Qi and blood" systems. There are 365 designated acupuncture points located along these meridians that can be used for stimulation through needles to balance and harmonize the yin and yang by relieving blockages in the flow of Qi [4]. This method of healing has been used to promote balance in and improve the functions of the body's organs.
Acupuncture needles are either manipulated manually or via an electrical stimulator, that is, "electroacupuncture" (EA). New methods for stimulating the acupoints include applying electric current to skin electrodes over the points, 1.1. Possible Mechanisms for the Effectiveness of Acupuncture on Opiate Addiction. The mesolimbic dopamine system originates in the ventral tegmental area (VTA) and projects to regions that include the nucleus accumbens and prefrontal cortex, which are believed to play a pivotal role in the development of opiate addiction [4]. Opiate abuseinduced changes in the levels of dopamine in the brain are associated with feelings of well-being and pleasure, providing positive reinforcement of continued opiate abuse [18,19]. Conversely, withdrawal from chronic opiate administration reduces dopamine outflow in the nucleus accumbens [20,21]. Opioid withdrawal causes dysphoria and significant distress, a state that addicts seek to avoid and one that can be a major motive for continuing opiate use (i.e., negative reinforcement) [22,23].
Many studies in animals and humans have demonstrated that acupuncture causes multiple biological responses [24]. Manual acupuncture (MA) and EA are capable of triggering a chain of events that can be understood through controlled experiments. The best-known mechanism is via endogenous opiates and their receptors. Different kinds of endogenous opiates, such as β-endorphin, enkephalin, endomorphin, and dynorphin, reportedly act as frequency-dependent factors in EA. EA of low frequency (2 Hz) accelerated the release of β-endorphin and enkephalin in the CNS whereas EA of high frequency (100 Hz) accelerated the release of dynorphin [25][26][27][28].
Early works have demonstrated the involvement of κ opioid receptors in the mechanism underlying the effects of acupuncture on morphine addiction. In 1993, Han and Zhang reported the effectiveness of EA on morphine abstinence syndrome in a rat experimental model. The authors found that 100 Hz EA produced a statistically significant suppression of wet shakes, teeth chattering, escape attempts, weight loss, and penile licking (P < 0.05) whereas 2 Hz EA produced a mild but significant suppression in escape attempts and wet shakes [29]. These results suggest that 100 Hz EA was far more effective than 2 Hz EA in suppressing withdrawal syndrome. Further studies suggested that EA suppresses opiate withdrawal syndrome by activating κ opioid receptors and dynorphin release [29][30][31][32][33].
Additionally, acupuncture affects the reinforcing effects of morphine. The method of conditioned place preference (CPP) is a commonly used animal model of drug craving [34]. Wang et al. reported that morphine-induced place preference in rats is significantly suppressed by 2 Hz EA and 2/100 Hz, but not at 100 Hz [35]. However, Shi et al. showed that 100 Hz EA significantly attenuated morphine-induced CPP, and this effect was completely blocked by δand κopioid receptor antagonists, suggesting that the anticraving effects induced by 100 Hz EA are mediated by the activation of δand κ-opioid receptors [36].
In 2008, Yang et al. reviewed the possible mechanism underlying the effectiveness of acupuncture in the treatment of drug addiction and this review provided clear evidence for the biological effects underlying the use of acupuncture to treat drug abuse [4]. This review provided a hypothetical model of the effects of acupuncture on dopamine release in the nucleus accumbens. Regarding positive reinforcement, acupuncture treatment activates GABA B receptors on the dopamine cell body and activates presynaptic κopioid receptors in the nucleus accumbens through dynorphin neurons, resulting in decreased dopamine release. Regarding negative reinforcement, acupuncture treatment stimulates enkephalin neurons in the hypothalamus and interacts with μ-opioid receptors to inhibit VTA GABAergic interneurons and thus increases dopamine release in the nucleus accumbens [4].
Recent basic studies further support the abovementioned theory and additionally suggest a role for brain-derived neurotrophic factor (BDNF) in this process. MA at Shenmen (HT7) points regulates the reinforcing effects of morphine via regulation of GABA receptors [37] and significantly suppresses morphine-induced increases in locomotor activity and Fos expression in the nucleus accumbens and striatum [38]. Further, results from several animal studies [39][40][41] showed that both 2 and 100 Hz EA facilitate the recovery of VTA dopaminergic neurons damaged by chronic morphine administration and upregulate BDNF protein levels in the VTA, suggesting Evidence-Based Complementary and Alternative Medicine 3 that the potential use of EA as a therapy for treating opiate addiction is associated with the activation of endogenous BDNF.
In summary, neurochemical and behavioral evidence have shown that acupuncture helps reduce the effects of positive and negative reinforcement involved in opiate addiction by modulating mesolimbic dopamine neurons. Moreover, several brain neurotransmitter systems involving opioids and GABA have been implicated in the modulation of dopamine release by acupuncture. However, many unanswered questions remain regarding the basic mechanisms of action of acupuncture. Future research could better determine the influence of acupuncture therapy on the regulation of dopamine and other neurotransmitters.
This paper provides an overview of trials that have investigated the clinical effectiveness of acupuncture in the treatment of opiate addiction. We here summarize the quality of the study design, types of acupuncture applied, commonly selected acupoints or sites of the body, and the effectiveness of the treatment in these trials.

Literature Search.
In April 2011, a literature search was performed using the following English language databases: PubMed and EBSCOhost. The first search keyword used was "acupuncture" and the second keyword used was either "heroin" or "opiate".

Inclusion and Exclusion Criteria.
We included studies that met the following criteria: (1) randomized control trials (RCTs) that adopted a double-blind, single-blind, or nonblind design and (2) participants met criteria for opiate/heroin dependence.

Data Extraction and Quality Assessment.
Clinical trials on the treatment of opiate/heroin dependence were selected based on the predetermined inclusion and exclusion criteria. Data were extracted from study reports by one reviewer and were verified by a second reviewer. The following key information was extracted from each study: first author, publication year, study design, sample size, characteristics of participants, main acupoints/sites selected, outcome measures, results reported, and adverse events.
We assessed the quality of the studies using the Jadad scale [42], 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 were considered of low quality whereas trials scoring 3-5 points were considered of high quality.

Results
An initial search identified 184 published articles from PubMed and 55 published articles from EBSCOhost. Only 10 published articles met our inclusion criteria and these were systematically reviewed ( Table 1). The other articles were excluded because they were not RCTs or included subjects without heroin or opiate addiction ( Figure 1).

Types of Studies.
Five studies mentioned the process of randomization. None of the studies mentioned the use of blinding on clinicians, subjects, or the raters of study outcomes. Four studies [45,47,48,50,51] were from Chinese journals.

Diagnostic Criteria and Characteristics of Participants.
Five studies [47,48,50,52]  Ten studies involving 1034 subjects (including those in intervention groups and in control groups) were enrolled, of which 711 cases were from China, 200 were from the USA, 83 were from the UK, and 40 were from Iran. Forty participants were HIV positive.

Outcome Measures and Effectiveness Assessment.
In most of the reviewed studies, the outcome measures included attendance rate, craving scale, and opiate withdrawal symptoms. Seven studies [43, 45-48, 50, 51] provided evidence for acupuncture as treatment for opiate addiction whereas 3 studies [44,49,52] were against the use of acupuncture to treat opiate addiction.

Adverse Effects or Events.
Most studies did not mention adverse effects or events, few studies described the monitoring of safety, and only 2 studies [43,47] reported adverse events including slight bleeding, mild nausea, dizziness, and mild dry mouth.

Main Acupoints/Sites Selected.
In the studies included in the review, several used a fixed set of acupoints or sites on their subjects and 1 study allowed some flexibility and needled additional points based on the symptom presentation of individual subjects. The 5 ear acupoints (sympathetic, shenmen, kidney, lung, and liver) were often used in the USA and UK. In China, the acupoints of Zusanli (ST36), Sanyinjiao (SP6), Hegu (LI4), and Neiguan (PC6) were most frequently used for the treatment of opiate addiction. A summary of the main acupoints or sites selected in the studies is presented in Table 2.

Discussion
Although many studies have reported positive findings regarding the use of acupuncture to treat drug dependence, the evidence for its effectiveness has been inconclusive and difficult to interpret [53]. There are few randomized controlled clinical trials of acupuncture treatment for opiate addiction, and the methodological methods used in several clinical trials of acupuncture treatment for opiate dependence can be criticized for their poor quality. The quality issues include the following: small numbers of patients, no control subjects, lack of randomized assignment, lack of details regarding specific point locations for needle insertion, and no specification regarding the degree of blinding among research subjects.
In this paper, we classified trials as having low quality if they lacked double-blinding, description of withdrawal, and description of randomization. The majority of low-scoring trials displayed positive results regarding acupuncture treatment for opiate addiction. Further, acupuncture treatment showed potential for preventing relapse and reducing the severity of withdrawal symptoms. Studies receiving a high methodological quality score produced interesting results. Two studies [44,52] received high methodological quality scores but failed to report auricular acupuncture effectively. These 2 studies produced negative results, reporting that auricular acupuncture had no effect on withdrawal severity, craving, and attendance when provided as an adjunct to methadone treatment services.
Four studies [43,44,49,52] used auricular acupuncture for the treatment of heroin addiction and 3 of these studies [44,49,52] did not report any clinical gains from acupuncture for the treatment of heroin addiction. Five studies [46-48, 50, 51] used body acupuncture with manual or electrical stimulation and all reported some clinical efficacy from the acupuncture for the treatment of heroin addiction. The single study that used HANS [45] for the treatment of heroin addiction reported a significant improvement in the severity of withdrawal syndrome.
Although most of the articles from China reviewed herein have favorable outcome, the type of intervention and needling methods were different between the studies from China and Western countries. Most studies from China used body acupuncture to treat opiate addiction whereas studies from the other countries used auricular acupuncture to treat opiate addiction. In addition, there are various differences Wells et al. [44] Zhang et al. [45] Montazeri et al. [46] Wu et al. [47] Wen et al. [48] Margolin et al. [49] Zeng et al. [50] Mu et al. [51] Bearn et al. [52] (1) Was the study described as randomized?
(2) Was the randomization scheme described and appropriate?
Adverse events associated with acupuncture are infrequently reported and only 2 studies reviewed herein [43,47] reported adverse events. Ernst and White [54] determined the range of incidence of adverse events associated with acupuncture and found that those most commonly reported were needle pain (1-45%), tiredness (2-41%), and bleeding (0.03-38%), whereas fainting and syncope were uncommon (0-0.3%), pneumothorax was rare, but feelings of relaxation were very common (86%).
Acupuncture is based on the complex TCM theory that an energy (Qi) flows through meridians in each organ and most acupoints are located along one of these meridians. Because diseases are caused by an imbalance or disturbance of Qi, needling at these acupoints can harmonize Qi and cure diseases. Our experience suggests that better therapeutic acupuncture effects are obtained by doctors with several years, or even decades, of clinical training. Without sufficiently trained practitioners, specific therapeutic results may be masked by nonspecific and even placebo effects. Most modern acupuncture trials provide qualification details of the practitioners that performed the therapies. In several trials [44,52], details of the practitioners' training were merely acceptable whereas other trials did not provide this information. Therefore, the results and conclusions of these trials do not totally represent clinical settings.
The weakness of this review is the lack of available high-quality data and the results should be interpreted with caution because of the lack of well-designed, high-quality randomized controlled studies. Many studies did not use standard treatment protocols, objective diagnostic criteria, standardized outcome measures, and effective assessment methods. The methodological quality and the description of the studies were poor in the majority of studies.
It is appropriate for a systematic review to calculate the results of each study identified by the study authors only when those studies are sufficiently comparable as to subjects, interventions, and outcomes, and similar enough in design. In addition, the effects of a study intervention on the consequent health or outcomes have to lie in the same direction or show homogeneity. Under these conditions, the individual estimates from each study can be combined to produce a pooled estimate of effect, which is usually more precise than the evidence provided by any of the individual studies. When these conditions cannot be met, it is difficult to interpret the combined findings from individual studies consisting of heterogeneous subjects, interventions, and outcomes.
Although the 10 studies identified by our systematic review shared the same design (randomized control trial), they differed in their inclusion criteria, mode of intervention, and outcome measures. In particular, although 5 outcome measures were used by more than one study (i.e., attendance rate, retention rate, urinalysis, cravings, and withdrawal symptoms), the operational definitions for these measures differed by duration and units of measure. This study heterogeneity prevented us from conducting a statistical analysis.

Conclusion
This review covered a wide body of Chinese and English research investigations into the use of acupuncture for the treatment of opiate dependence from the early 1970s up to 2011. After 35 years of active research by both Asian and Western scientists, this review cannot be used to establish the Evidence-Based Complementary and Alternative Medicine 9 efficacy of acupuncture in the treatment of opiate addiction because the majority of these studies were classified as having low quality. Although this review may provide a basis for clinicians and future research, future well-designed RCT studies are needed to confirm the efficacy of acupuncture in the treatment of opiate addiction.