*4.2. Implications for Clinical Practice and Suggestions for Further Research*

The mechanism and therapeutic effect of acupuncture on PD have been elucidated in several studies. In a PD animal model, the expression of tropomyosin receptor kinase B (trkB) was increased in the ipsilateral substantia nigra, and a neuroprotective effect on neuronal cell death was revealed [51]. It also exhibits dopaminergic neuroprotective effects by inducing hypothalamic melanin-concentrating hormone biosynthesis [52]. As a result, it is possible to improve motor behavior while reducing the loss of dopaminergic neurons [51]. In a mechanistic study with functional MRI, acupuncture treatment for patients with PD demonstrated that the putamen and primary motor cortex were activated, and motor function was improved [51]. The mechanism of BVA has also been studied. Apamin toxin contained in BEEV is a polypeptide neurotoxin that blocks Ca2+ activated K + (SK) channels and induces hyperpolarization of dopaminergic neurons, thereby partially rescuing dopaminergic neurons in dissociated midbrain cell cultures [53]. BVA increases the size and number of neurons and striatal dopamine and protects dopaminergic neurons. Therefore, when BEEV is used alone or in combination with conventional drugs for PD, neuronal degeneration is alleviated, and movement disorders are reduced [54]. Several systematic reviews and meta-analyses of RCTs have also been published about the effect and safety of several acupuncture treatment modalities on PD [13,16,17,55].

However, it is unclear which acupuncture modality has a better effect and should be considered in clinical practice and research on PD. Therefore, we performed this NMA to help clinicians and researchers decide which acupuncture modality to use for PD. Although several NMA studies on acupuncture for various diseases have been reported [56–58], this is the first NMA study of acupuncture on PD. In our study, BEEV seems to be the best therapeutic option for motor symptoms and activities of daily living in patients with PD. However, the 95% CI overlapped different acupuncture modalities. Therefore, caution should be exercised when applying the results of this study to clinical practice and clinical research. In terms of effect size, the minimal clinical important differences (MCIDs) of the UPDRS motor scores were 2.5 points (minimal effect), 5.2 points (moderate effect), and 10.8 points (large effect) [59]. It was similar (approximately 5–7) in other MCID studies on the UPDRS III scores in patients with PD [60–62]. Considering the previous results of the MCID study, our results for the BEEV group showed a clinically significant moderate effect. The effect sizes of ELEC and MANU existed between minimal and moderate effects.

From a clinical perspective, even though BEEV might be the best option for motor symptoms and activities of daily living, MANU/ELEC might be an appropriate option for several motor symptoms [63]. In the presence of severe tremors, it may be difficult to use ELECs in the distal extremities. Therefore, physicians can try electroacupuncture treatment using acupuncture points on the scalp. BEEV might be inappropriate in some cases due to the risk of AEs, such as anaphylaxis [64]. In our results, MANU and ELEC had the best effect after BEEV in UPDRS-II and III. Therefore, if it is difficult to apply BEEV due to Aes, MANU or ELEC could be used as an alternative approach. However, the superiority between MANU and ELEC could not be determined in our study. In the sensitivity analysis, after excluding a long-term follow-up manual acupuncture study [44], ELEC was found to be better than MANU in UPDRS-III. Therefore, it might be possible that the treatment dose (number of sessions) might be an important factor for the therapeutic effect, but as the number of RCTs included in this study was relatively small, we could not conduct further analysis. As head-to-head comparison studies on ELEC and MANU are not common, meta-regression analysis or real-world evidence-based research with health insurance data are needed to address this issue. In summary, when deciding on the acupuncture treatment strategy for patients with PD in clinical practice, we need to consider several factors, such as applicability, adherence, AEs, and target symptoms. In real-world clinical practice, as an overlap of 95% CI of the effect size is clearly visible, it is recommended that BEEV combined with MA with/without electrical stimulation is recommended. Based on the results of this study, in clinical practice, we recommend using electroacupuncture on GB20 (Fengchi) and GB34 (Yanglingquan) for approximately 20–30 min in patients with PD from a clinical point of view. Since bee venom is a natural toxin, in terms of safety, therapeutic dosage is very important. In our study, the total amount of BEEV per session and total number of treatment sessions applied in our review were 100 µg (in 1 mL of NaCl 0.9%) for 11 sessions [39] and 50 µg (in 1 mL of NaCl 0.9%) for 16 sessions [41], respectively. With regard to safety, attention should be paid to side effects (such as anaphylaxis) when higher doses of BEEV than those reported in this study are applied. In addition to predictable dose-dependent side effects, non-predictable side effects due to individual sensitivity should also be considered.

Interestingly, the combined treatment of sham acupuncture with conventional medicine group (SHAM) was superior to the conventional medicine alone group (CONV). Placebo acupuncture is known to have a larger non-specific effect than other physical and pharmacological placebo modalities [65]. Sham acupuncture is known to be more effective than usual care or wait-list control groups for musculoskeletal diseases, such as non-specific low back pain [66]. Our study suggests that sham acupuncture might also have considerable non-specific effects on degenerative neurological diseases, such as PD. Therefore, a sham acupuncture-controlled design might underestimate the effect of acupuncture treatment. A pragmatic clinical study on comprehensive acupuncture treatment (combining ELEC, MANU, and BEEV) compared to an active control group (such as rehabilitation, medication,

qi-gong) might be a more appropriate design to address physicians' questions about which intervention should be added to CM.
