Effectiveness of acupuncture in the management of restless leg syndrome: a systematic review and meta-analysis

Introduction

Restless leg syndrome (RLS) is a “movement-responsive nocturnal focal akathisia with dysesthesia” (1) characterized by an urge to fold and unfold the legs rapidly accompanied by an unpleasant sensation that interferes with sleep. These symptoms, which most often arise at night, are worse at rest and are relieved upon moving legs or walking (2,3). There are 2 forms of RLS: primary RLS has a strong hereditary background and onsets early in life to peak at an age of 20 years. Up to 40–60% of individuals with RLS have a family history of RLS. Secondary RLS is an adult condition and appears later in life. It is characterized by sporadic symptoms with slower regression which may also be associated with peripheral neuropathy (3).

The condition of RLS is under-diagnosed. The prevalence of RLS is reported to be between less than 1% to 15% in various parts of the world (11.4% for Swedish women and 5.8% for Swedish men, 10.8% for French women and 5.8% for French men, 9.8% for German elderly 65–83 years old, 10% in Canada, and 1% in Singapore) (4). RLS has been found to be associated with risk of cardiovascular disease (CVD) even after controlling for age, gender, race, body mass index, systolic blood pressure, antihypertensive drug use, diabetes, cholesterol, smoking, and apnea-hypoapnea index (5,6). Insomnia and daytime distress have also been found to be significantly associated with RLS (7). Age, pregnancy, lower socioeconomic status, low iron levels, poor health, poor mental health, Parkinson’s disease, and end-stage renal disease have been identified as the risk factors for RLS (3).

Dopaminergic drugs such as levodopa are the first-line treatment for RLS (8). The analogues of gamma-aminobutyric acid such as gabapentin have been shown to be safe and efficacious in treating RLS of hemodialysis patients (9,10). Opioids, benzodiazepines, 4-phenyl-piperidine analogues, and alpha-2 adrenergic receptor agonists are also used for RLS treatment (11). Repetitive transcranial magnetic stimulation, pneumatic compression devices, counter-strain manipulation, infrared therapy, vibration pads, yoga, cryotherapy, and acupuncture are among the notable non-pharmacological treatments of RLS.

Acupuncture is an important component of traditional Chinese medicine (TCM) which is used to treat an array of health conditions. Insertion of acupuncture needles in various acupoints targeting energy channels is postulated to restore a balance that maintains health (12). Several studies have reported the outcomes of acupuncture in the management of RLS either as sole treatment or in combination with other related therapies, but the designs and the outcomes vary across these studies which necessitates a systematic review of this topic. The aim of the present study was to evaluate the effectiveness of acupuncture for the treatment of RLS by reviewing the outcomes of relevant studies in literature. We present the following article in accordance with the PRISMA reporting checklist (available at https://dx.doi.org/10.21037/apm-21-2309).

Methods

Eligibility criteria

The inclusion criteria of the present study were: a study (I) evaluated the effectiveness of acupuncture either alone or with other related therapies for the management of RLS; (II) reported quantitative outcomes depicting the efficacy; and (III) reported the outcome measure/s which could depict the effectiveness in alleviating the symptoms of RLS such as sleep quality, pain, activity, and so on. The exclusion criteria were: other TCM methods were utilized without acupuncture; reported the outcomes without differentiating acupuncture from other therapies; or did not report quantitative information.

Literature search

For literature search, electronic databases consulted were: China National Knowledge Infrastructure (CNKI), Google Scholar, PubMed, and Wangfang. The important medical subject headings and keywords used as different phrases were: restless leg syndrome, RLS, acupuncture, acupoints, electro-acupuncture, hydro-acupuncture, tuina, massage, moxibustion, acuinjection, warm needle, stone scraping, traction, plum-blossom, and cupping. The search was delimited to original research papers published in English or Chinese language before October 2020.

Data and analyses

Important data pertaining to the demographic and clinical characteristics of patients, treatments, outcome measures, and outcomes were extracted from research articles by 2 authors independently. Inter-rater reliability was high (Cohen kappa =0.94). The primary endpoint for the present study was ‘total effective rate’ defined as the sum of ‘cure rate’, ‘marked effect rate’, and ‘effective rate’ of the treatment, where ‘cure’ was the disappearance of the symptoms of RLS with sufficient sleep (≥6 h); ‘marked effect’ was remission of the symptoms of RLS with almost normal sleep (5–6 h); ‘effective rate’ was relieving of the symptoms of RLS with alleviation of insomnia (4–5 h sleep); and ‘ineffective rate’ meant no remission of the symptoms (13). Additional endpoints were the changes in the International Restless Legs Syndrome Rating Scale score, Epworth Sleep Scale score, and the Pittsburgh Sleep Quality Index score.

For achieving the pooled effect size of the percent effectiveness rates, random effects meta-analyses were performed with Stata software (version 12; Stata Corp.; College Station, TX, USA) using DerSimonian-Liard method where the standard errors of the effectiveness rates were derived from sample sizes.

Statistical analysis

For the estimation of the change in the International Restless Legs Syndrome Rating Scale scores, a meta-analysis of mean differences was performed with Cochrane Review Manager software (version 5.3) using random-effects inverse-variance method.

Quality assessment of the included studies was performed with Newcastle-Ottawa Scale for the assessment of quality of observational cohort studies. Between-study inconsistency in outcomes (statistical heterogeneity) was estimated with I² index and sensitivity analyses were performed. Begg’s test was performed to assess publication bias.

Results

A total of 18 studies (13-30) were included in this meta-analytical review (Figure 1). In these studies, 640 patients with RLS were treated with acupuncture either alone or in combination with any other therapy and 447 patients were treated with non-acupuncture control therapies. A total of 10 studies performed acupuncture alone and rest of the studies performed acupuncture in combination with other therapies including moxibustion (n=3), cupping (n=1), injection (n=1), TCM herbal fumigation (n=1), gabapentin (n=1), and levodopa (n=1). Control treatments included levodopa with or without benserazide (n=5), non-acupuncture TCM (n=1), alprazolam/oryzanol (n=1), gabapentin (n=1), and vitamin B_1/12-Danshen (n=1). Quality of the included study was low to moderate in general (Table 1).

Figure 1 Flowchart of the study screening and selection process. TCM, traditional Chinese medicine.

The total effective rate was 90.5% [95% confidence interval (CI): 86.2% to 94.9%] in patients treated with acupuncture either alone or in combination with other related treatments and 65.8% (95% CI: 52.1% to 79.5%) in patients treated with non-acupuncture therapies (Figure 2). Cure, marked effect, and effective rates were 47.8% (95% CI: 38.3% to 57.3%), 27.4% (95% CI: 20.3% to 34.8%), and 24.2% (95% CI: 16.9% to 31.5%) in patients treated with acupuncture either alone or in combination with other treatments and 21.7% (95% CI: 20.7% to 22.7%), 28.0% (95% CI: 20.0% to 32.9%), and 22.3% (95% CI: 17.0% to 27.6%) in patients treated with non-acupuncture therapies, respectively. The ineffective rate was 4.7% (95% CI: 4.3% to 5.0%) in the acupuncture group and 32.9% (95% CI: 22.2% to 43.7%) in non-acupuncture groups.

Figure 2 Forest graph showing the total effective rates of treated and control groups. Columns after treatment are the percent values of cure, marked effect, effective, and ineffective rates. ACU, acupuncture; BENZ, bezodiazepine; DOPA-based therapy, dopamine, INJ, injection; L-DOPA, levodopamine, Mod, modern; MOX, moxibustion; St-ws, streaming and washing; TCM, traditional Chinese medicine; Trad, traditional; Vit, Vitamin.

There was no difference in the total effective rate between acupuncture alone [91.6% (95% CI: 90.6% to 92.6%)] and acupuncture in combination with other therapies [92.2% (95% CI: 90.9% to 93.5%)]. Cure rate was higher in patients treated with acupuncture alone [51.1% (95% CI: 44.4% to 57.8%)] than in those treated with acupuncture in combination with other related therapies [44.1% (95% CI: 25.9% to 62.2%); Figure 3], but marked effect rate was lower in patients treated with acupuncture alone [16.1% (95% CI: 11.0% to 21.2%)] than in those treated with acupuncture in combination with other related therapies [38.7% (95% CI: 24.0% to 53.4%); Figure 4]. There was not much difference in the effective rate [24.8% (95% CI: 16.5 to 33.1) of acupuncture alone vs. 23.5% (95% CI: 12.5% to 34.6%) combination] but ineffective rate was slightly higher in the acupuncture group [9.22% (95% CI: 5.36% to 13.1%)] than in acupuncture in combination with other therapies [2.48% (95% CI: 2.12% to 2.84%)].

Figure 3 Forest graph showing the cure rates of patients treated with acupuncture alone and acupuncture in combination with other related therapies.

Figure 4 Forest graph showing the marked effect rates of patients treated with acupuncture alone and acupuncture in combination with other related therapies.

A meta-analysis of 2 studies showed significant improvement in International Restless Legs Syndrome Rating Scale scores after acupuncture treatment [mean change from baseline −9.45 (95% CI: −18.42 to −0.49); P=0.04; Figure 5].

Figure 5 Forest graph showing the meta-analysis of mean change from baseline in International Restless Legs Syndrome Rating Scale score after acupuncture treatment.

Discussion

In this meta-analysis, we have found that acupuncture, especially in combination with other related therapies, was more effective than non-acupuncture therapies for RLS. However, some methodological issues kept this evidence at a low level. Only a few studies reported information about the number of acupuncture sessions performed; follow-up ranged from 1 month to 2 years; and majority of the included studies reported effectiveness rates without symptomatic improvement indices. Thus, well-designed randomized controlled trials are needed to confirm the findings of the present study.

Acupuncture is one of the important components of TCM that is recognized as an efficacious and safe treatment option for many health conditions including neurological and psychiatric diseases. Acupoints such as Shenshu (BL23), Xuehai (SP10), Chenshan (BL57), Zusanli (ST36), Sanyinjiao (SP6), and Taixi (KD3) are commonly involved in the treatment of RLS (31). As far as the mechanism of action is concerned, it is suggested that acupuncture may target the autonomic nervous system to manifest its effects. Acupuncture at Jianshi-Neiguan acupoints (PC5 to PC6 below median nerve) inhibits the sympathetic nerve and slows down excitatory cardiovascular reflexes via the opiate pathways which may trigger the inflammatory reflex and immune system (21). Moreover, acupuncture is reported to reduce oxidative stress in brain parts and promotes neuroprotection by increasing levels of BDNF, GDNF, and cyclophilin (32). Besides reducing oxidative stress, acupuncture treatment is also found to exhibit antiapoptotic and anti-inflammatory effects (33).

Acupuncturists emphasize that Yang deficiency in the legs causes symptoms like sensation of cold or fatigue in lower extremity whereas Yang stagnation which may represent disturbance of Shao Yang affects muscle tension. It is suggested that for improving Yang deficiency in the legs, needling in Tianshu (ST25) and Juxu Shanglian (ST37) acupoints can be useful whereas for the improvement in Yang stagnation, the acupoints Zhongdu (GB32) and Xiaoluo (TB12) are needed to be activated. Qi stagnation may also cause restlessness in the legs which can be treated by needling Dadun (LR1) and Yanglingquan (GB34). Ying deficiency and Yang stagnation leads to symptoms like cramps, cold feet, insomnia, urinary inconsistency, muscle tension, and urge for motion. Acupoints useful to address such symptoms are Zhongdu GB32 and LR6 (15). According to Pan et al., liver yin and xue control lower limb activity at night and are also responsible for body and brain relaxation. When yin and xue become deficient, which may also be associated with qi imbalances, the conditions like RLS develop (21).

Among the included studies, Dai et al. (14) used Biguan (ST31) acupoint located on the line joining anterior superior iliac spine and the external edge of patella to dilate blood vessels and to activate qi which was substantiated by the moxibustion heat conducting down the leg. Liu (19) who treated 49 RLS patients found a total eradication of symptoms in 41 patients and relief was persistent by 6-months follow-up. Liu (19) used Yanglingquan (GB34), Jinggu (BL64), Chengshan (BL57), Chengjin (BL57), Shangju (SP5), Ganshu (BL18), Shenshu (BL23), Taixi (KI3), Xuehai (SP10) and Sanyinjiao (SP6) acupoints. Pan et al. (21) used Shenshu (BL23), Mingmen (DU4), Xuehai (SP10), Chenshan (BL57), Taichun (LR3), Zusanli (ST36), Sanyinjiao (SP6), and Taixi (ST36) acupoints to apply standard acupuncture and found it effective in improving symptoms and sleep quality. Raisi et al. (22) who treated RLS patients with acupuncture in combination with gabapentin, used Shenshu (BL23), Ganshu (BL18), Chenshan (BL57), Jinggu (BL64), Zusanli (ST36), Liangqiu (ST34), Shangqiu (SP5), Xuehai (SP10), Shanyijiao (SP6), Taixi (KI3), Yanglingquan (GB34), Xuanzhong (GB39) acupoints and found that the combinational therapy had some additive effect in comparison with gabapentin monotherapy.

In the present study, a meta-analysis of 2 studies found a statistically significant improvement in International Restless Legs Syndrome Rating Scale scores 6–8 weeks after acupuncture treatment. Pan et al. (21) also found changes in the Epworth Sleep Scale score, and sleep mean activity to be significantly better in acupuncture group than in control group 6 weeks after treatment. Raissi et al. (22) found a significant difference in the Pittsburgh Sleep Quality Index score between acupuncture and control groups 8 weeks after treatment.

Some other studies have also reported that acupuncture is an effective treatment option for RLS. In a retrospective analysis of 19 patients, Cripps (34) found acupuncture efficacious in alleviating the symptoms of RLS. He used BL57 and LR3 acupoints bilaterally and stimulated these with electroacupuncture for 20–30 minutes. Greater improvement was noticed in patients who had not received previous dopaminergic therapy. In a single-blind, randomized controlled trial, 60 hemodialysis patients with RLS received 12 sessions of near infrared (940 nm) treatment to acupoints in the lower limb 3 times a week. In this study, clinically significant improvement was observed, but upon discontinuation the effect was diminished (35). Describing 2 cases with RLS who were treated with acupuncture, Fukutome (36) reported that 4W-acuinjection in Zulinqi (GB41), Kunlun (BL60), Zusanli (ST36), and Sanyinjiao (SP6) acupoints led to immediate relief in the form of a calm sensation and cessation of involuntary movements in legs.

A recent review found that besides acupuncture, other non-pharmacological treatments including repetitive transcranial stimulation, precise physical exercises, sequential pneumatic compression devices, use of counterstain techniques, and infrared exposure also remain effective in relieving RLS symptoms (37). Regardless of the treatment strategy, several factors can have impacts on the incidence, prevalence, and treatment of RLS. Among the socioeconomic factors, female gender, unemployment, retirement, less education, and low income are found to be associated with RLS (38). Depression is frequently associated with RLS. In a study of community-dwelling elderly, 1 in 8 individuals with RLS had depression whereas 1 in 25 individuals without RLS had depression. Men with RLS were more likely to take antidepressant medication (39). There is evidence to suggest that the use of antidepressant medication can aggravate RLS (40).

Acupuncture effects observed in trials are often suspected for the presence of placebo effect or expectation bias (41,42). However, a recent randomized controlled trial found that raising expectations of the participants before acupuncture treatment had no effect on the outcomes, but the incidence of side effects was significantly more in the group that was intensely briefed about side effects possibilities (43). It is suggested that addition of a sham-acupuncture arm in acupuncture trials can yield a better clarity of the outcomes (44).

Among the notable limitations of the present study, less availability of non-Chinese literature is an important consideration. We observed high statistical heterogeneity in the pooled analysis which could be attributed to the use of many types of controls and many therapeutic combinations with acupuncture. To test sources of heterogeneity, we performed meta-regression analyses but neither study sample size nor follow-up duration, or year of study publication were significantly associated with total effective rate. Definitions of effectiveness rates were not given by most of the included studies and there may have been some between-studies deviation in measuring the actual effect of therapy.

Conclusions

According to this meta-analysis, acupuncture either alone or in combination with other related therapies is an effective treatment option for RLS. Cure rate significantly differed between acupuncture and non-acupuncture therapies (48% vs. 22%). Several limitations, including the variations in combinational and control treatments, methodological inconsistencies, variation in follow-up durations, and the lack of effect measurement standards kept the level of this evidence low. Therefore, randomized trials with better designs and suitable controls especially with a sham-acupuncture arm are required to seek refined evidence.

Acknowledgments

Funding: None.

Footnote

Reporting Checklist: The authors have completed the PRISMA reporting checklist. Available at https://dx.doi.org/10.21037/apm-21-2309

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://dx.doi.org/10.21037/apm-21-2309). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All analyses were based on previous published studies, thus no ethical approval and patient consent to participate were required.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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(English Language Editor: J. Jones)