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Acupuncture therapy is widely used in the clinic, and its therapeutic effects have been proven by numerous studies. The dose–effect relationship of acupuncture is a fundamental aspect of the acupuncture research system. Recent studies found that different acupuncture dosages altered study results directly, indicating the importance of screening the optimal stimulation dosage. However, the system for studying the acupuncture dose–effect relationship is still in its infancy, and the methodology of the system needs to be improved. This review aimed to define the factors impacting acupuncture “dosage” and “effect,” and to improve the methodological system for research on the dose–effect relationship of acupuncture. By summarizing the current findings of acupuncture dose–effect studies, we discussed the vital acupuncture parameters and methodological problems that influence the relationship between acupuncture dosage and its effects. These factors consist of specific influencing factors (acupoint selection, acupuncture manipulation parameters, de qi response) and nonspecific influencing factors (comparison selection, blinding procedure, patient expectancy). Our perspectives offer suggestions for the design of acupuncture dosage– effect trials. Further studies need to be conducted to establish the methodological system and provide systematic evidence of the acupuncture dose–effect relationship. Keywords: Acupuncture, Dose–effect relationship, Methodology, Review Graphical abstract: http://links.lww.com/AHM/A37  of the body . The stimulation dosage is a fundamental Introduction element of acupuncture, and is a vital facet of acupunc- Acupuncture therapy originated from traditional ture manipulation, which determines the therapeutic Chinese medicine and is widely used as the comple-  effects of acupuncture . The acupuncture dose–effect  mentary and integrative therapies over the world . relationship was formulated more than 2,000 years ago Through needle manipulations, acupuncture is used to in China. In the 1970s, academician Shi Xuemin defined regulate the qi and blood, and balance yin and yang the concept of the acupuncture dose–effect relationship, which contains the acupuncture method and the stimu- Boxuan Li, Menglong Zhang, and Sakhorn Ngaenklangdon  lation dosage of acupuncture . By conducting a series contributed equally to this work. of clinical trials and experimental research, academi- First Teaching Hospital of Tianjin University of Traditional Chinese cian Shi Xuemin preliminarily revealed the dose–effect Medicine, Tianjin, China; National Clinical Research Center for relationship between manipulation parameters and the Chinese Medicine Acupuncture and Moxibustion, Tianjin, China; therapeutic effects of acupuncture, and established a Tianjin University of Traditional Chinese Medicine, Tianjin, China; 4 system for studying the acupuncture dose–effect rela- TCM Lecturer, Faculty of Traditional Chinese Medicine, Nakhon tionship. Exploration of the acupuncture dose–effect Ratchasima College, Thailand. relationship can help to define the optimal parameters * Corresponding author. Shizhe Deng, First Teaching Hospital of for acupuncture, which can provide the basis for the Tianjin University of Traditional Chinese Medicine, National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, standardization of acupuncture therapy. Additionally, it Tianjin 300381,China, E-mail: firstname.lastname@example.org; Zhihong is of great significance for the international promotion Meng, First Teaching Hospital of Tianjin University of Traditional of acupuncture use. Chinese Medicine, National Clinical Research Center for Chinese According to the Consolidated Standards of Reporting Medicine Acupuncture and Moxibustion, Tianjin 300381,China, E-mail: Trials statement, sufficient details to allow replication is email@example.com.  required when describing an intervention . Acupuncture Copyright © 2022 Tianjin University of Traditional Chinese Medicine. therapy should thus be accompanied by quantified This is an open-access article distributed under the terms of the manipulation details. To guide the reporting of acupunc- Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download ture studies, the STandards for Reporting Interventions and share the work provided it is properly cited. The work cannot be in Clinical Trials of Acupuncture (STRICTA) stressed changed in any way or used commercially without permission from the the importance and necessity of reporting details of journal. acupuncture intervention, which led to improvements Acupuncture and Herbal Medicine (2022) 2:4 in the quality of trials reporting on acupuncture. In Received 8 September 2022 / Accepted 11 October 2022 2010, the revised STRICTA was published, which http://dx.doi.org/10.1097/HM9.0000000000000050 focused on the nonpharmacologic treatment properties 221 Li et al. • Volume 2 • Number 4 • 2022 www.ahmedjournal.com  of acupuncture . The description of needling details contradictory conclusions. It also facilitates establish- has been extended into 6 sub-items including the num- ing the mechanistic pathways underlying acupuncture ber of acupoints, acupoint selection, needle depth, de qi effects. However, studies of acupuncture dose–effect response, needle stimulation, needle retention time, and requires a distinct methodological system. needle type. In terms of the treatment regimen, the num- The objective of this review is to identify crucial fac- ber, frequency, and duration of treatment sessions are tors that influence acupuncture dosage, acupuncture required to be reported. effects, and their relationship, and to propose practica- In the same way, pharmaceutical treatment is estab- ble solutions from a study methodological point of view. lished with the optimal appropriate dosage, treatment We hope to provide up-to-date evidence for establish-  frequency, and treatment duration . The concept of ing a system for evaluating the acupuncture dose–effect acupuncture “dose” is the true stimulation dosage of relationship. acupuncture, which means the aggregation of individual  sessions over the treatment course . Each acupuncture Vital methodological strategies in studies of the treatment session is mechanical stimulation, and the dos- acupuncture dose–effect relationship age is dependent on a compound of parameters involv- ing needling depth, needling direction, needling depth, Specific factors influencing the dose–effect relationship manipulation frequency, the frequency of acupuncture Acupoint selection session, and the whole treatment duration. For clinical Acupoints are the basic components of the meridian sys- application, the dose has three important aspects: the minimal stimulating dosage that elicits sufficient ther - tem and are the minimal unit that contributes to the  acupuncture effect. According to traditional Chinese apeutic effect , the maximal stimulating dosage that  avoids adverse reactions , and the optimal stimulating medicine theory, each acupoint has particular therapeutic  properties, and the combinations of different acupoints dosage for the specific disease . As for the “effect” in the clinical study, it is related to the therapeutic effect such as show different therapeutic effects. Currently, studies of the acupuncture dose–effect relationship typically uses a the modulation of dysfunction and the recovery of defor- mity. The differential stimulation dosage on acupoints single acupoint or a particular acupoint regimen. Single acupoint studies usually choose a specific acupoint has a diverse influence on the downstream conduction pathways via the nerve system, endocrine system, and whose therapeutic effects have been proven based on a sufficient number of clinical cases. For instance, in the immune system, or has a differential impact on the tar- get organs directly, which changes the therapeutic effects. study of acupuncture at ST36 (Zusanli) for sepsis, exper- imental research has presented the mechanisms at mol- While in the experimental research, the “effect” refers to  the whole process of effective pathways from the initial ecule, cell, tissue, organ, and whole-body levels . One  distinct strength of single acupoint studies is that this evoking effect of acupoint , the amplification effect of  the signal pathway conduction , the modulation effect can reduce bias caused by other acupoints, hence reveal-  ing the real effects of the selected acupoint. Moreover, of the neuro-endocrine-immune network , and the reg-  ulation effect of organs . the intervention procedure is less complicated than acu- point combination studies. However, single acupoints In an acupuncture dose–effect relationship study, mul- tiple factors are associated with dose and effect. They might not meet the clinical requirements: the combina- tion of other acupoints with similar effects is typically are divided into specific influencing factors (acupoint selection, acupuncture manipulation parameters, de qi necessary. In acupoint combination studies, researchers mostly focus on comprehensive effects, including the response) and nonspecific influencing factors (compar - ison selection, blinding procedure, patient expectancy) clinical therapeutic effects and the mechanistic path- ways. The relationship between acupoint selection and in this review. Acupuncture manipulation parameters and acupoint selection are fundamental elements of the acupuncture dose–effect relationship is demon- strated in Figure 1. Generally speaking, both single acu- acupuncture dosage. From a methodological point of view, having quantified manipulation parameters ben- point studies and acupoint combination studies should consider different dosages as variables in acupuncture efits the repeatability of acupuncture research, improv- ing the intervention consistency in multi-center studies, dose–effect relationship studies. These dosage variables could involve manipulation parameters, including nee- which helps to reduce the heterogeneity arising from  acupuncture operations . In terms of clinical effect, the dle depth, needle twirling frequency (or electroacupunc- ture frequency), needle direction, needle retention time, direct impact of acupuncture manipulation parameters on changes in clinical effects have been proven, which and treatment sessions. We analyzed these manipulation parameters in the following part. emphasizes the significance of exploring the optimal [16–19] acupuncture parameter . For instance, a previous study demonstrated that changes in acupuncture twirl- Acupuncture manipulation parameters  ing frequency evoked different mechanistic pathways . A series of randomized clinical trials (RCTs) with differ- The acupuncture manipulation parameter is the core factor ences in acupuncture treatment sessions presented con- that influences the stimulation dosage, and thus alters acu- trasting results on the effects of acupuncture for treating puncture effects directly. Based on current study evidence, [21-22] knee osteoarthritis (KOA) . Considering the diverse we illustrate the relationship between manipulation param- study results, adequate acupuncture dosage is of great eters and effects such as needle depth, needle manipulation significance. Therefore, the exploration of the acupunc- frequency (or electroacupuncture frequency), needle direc- ture dose–effect relationship is a potent way to address tion, needle retention time, and treatment sessions. 222 Li et al. • Volume 2 • Number 4 • 2022 www.ahmedjournal.com to reinforce acupuncture stimulation, and the manipula- tion frequency is a vital parameter. Recent studies have found that different acupuncture manipulation frequen- cies exert effects via different mechanistic pathways. An  animal experiment showed that , compared with manual acupuncture of twice per second, a higher acupuncture twirling frequency (four times per second) had a stronger analgesic effect. To investigate the analgesia mechanism, the primary sensory afferent neuron type was examined and revealed that an acupuncture twirling frequency of four times per second activated C-fiber neurons, while that of twice per second stimulated A-fiber neurons. After needle penetration and acupuncture manipula- tion, the duration of retention of the needle is another essential aspect of acupuncture therapy. Considering clinical feasibility, the retention time usually ranges from  10 minutes to 60 minutes . The disease type is a vital factor that affects the retention time. For example, in a study of different acupuncture retention times in Knee osteoarthritis(KOA) patients, those who received 45-min- ute retention after needle penetration showed a greater clinical improvement than those with a retention time Figure 1. Relationship between acupuncture dosage and effect.  of 30 minutes . A functional digestive disease study Acupuncture dosage-related factors include acupoint selection, treat- ment session, needle manipulation frequency, needle retention time, showed that, after needling at GB34 (Yanglingquan) needle direction, and needle depth. in chronic cholecystitis patients, a 40-minute retention yielded a greater effect in reducing the high-tension state  Needle depth affects the acupuncture effects by stim- of the gallbladder than no needle retention . ulating specific anatomical tissues. For example, super - In terms of acupuncture treatment sessions, a few stud- ficial acupuncture at RN23 (Lianquan) stimulates the ies have used different numbers of treatment sessions for cutaneous nerve of the neck, while in-depth acupuncture comparison. However, by analyzing individual acupunc- stimulates the thyrohyoid muscle, the tongue muscle, ture studies related to a similar disease, we found that the the superficial anterior jugular vein, the superior thyroid number of treatment sessions influenced the acupuncture artery, the superior thyroid vein, and the hypoglossal effects directly. In 2014, a clinical study of acupuncture  nerve . In a study of the effects of acupuncture at RN 23 for chronic KOA showed that after 8 to 12 sessions of on dysphagia, a deep acupuncture group (needle depth of treatment, there was no significant difference between the  60–70 mm) showed greater effects in terms of improved acupuncture group and the sham acupuncture groups . clinical symptoms than did a shallow acupuncture group In contrast, another study performed in 2019 proved that  (needle depth of 10–20 mm) . However, other studies 24 sessions of electroacupuncture had significantly dif- obtained variable results, indicating that the optimal ferent effects than sham acupuncture in terms of reduc-   needle depth varies with the disease severity and with ing pain and improving KOA patients’ function . These  the patients’ condition . three studies have proven that different number of acu- Acupuncture direction is closely associated with the puncture sessions can lead to contrasting results. The  effects and safety of acupuncture therapy . It has been existing evidence in analgesia studies has proven that an described in detail in China since ancient times. The acu- adequate number of acupuncture sessions underlies the  puncture direction is flexible and is changed for differ - therapeutic effect ; however, the optimal number of ent diseases. According to traditional Chinese medicine acupuncture sessions needs to be explored further. theory and the meridian system, acupuncture direction These previous studies have typically focused on a sin- can be determined by the meridian trajectory and the gle acupuncture manipulation parameter, and revealed body projection area of the disease. In the modern med- its dosage relationship with acupuncture effects. In ical system, studies of acupuncture direction have been clinical application, however, acupuncture therapy is a extended, taking into account the anatomical charac- comprehensive operation involving multiple manipula- teristics of the nervous system and the musculoskele- tion parameters. Hence, it is essential to conduct a study  tal system . A previous study has shown that using of combined manipulation parameters. Previous studies the opposing directions of acupuncture (following the have reported using a combination of different acupoints meridian trajectory or in the inverse direction) at LI4 and needle manipulation frequencies, needle retention  (Hegu) caused different therapeutic effects in terms of time, and needle manipulation frequency . In animal  the recovery of central facial palsy . Furthermore, a studies, we chose needle manipulation frequency (once safety analysis showed that both acupuncture directions per second, twice per second, three times per second) at GB20 (Fengchi) were safe among patients with poste- and needle retention time (5 seconds, 60 seconds, and  rior circulation ischemia vertigo . 180 seconds) as intervention variables in middle cere- There are several manipulations used in acupuncture. bral artery occlusion model rats, comparing the combi- The basic motions include lifting, thrusting, and twirling. nation effects in nine groups. The results indicated that After needle penetration, needle manipulation is believed the most powerful factor influencing the acupuncture 223 Li et al. • Volume 2 • Number 4 • 2022 www.ahmedjournal.com effect is the retention time, while the optimal parameters The neuro-endocrine-immune network is the fourth were a manipulation frequency of three times per second part. In the dose–effect relationship, the de qi sensation  with a 60-second retention . Additionally, this study represents the dosage of acupuncture stimulation, and showed that the interaction between needle manipula- changes in the stimulation alter the therapeutic effects tion frequency and needle retention time altered the acu- by activating different acupoint tissue, signal pathways, puncture effect. Considering these aspects, future studies central neural integration, and neuro-endocrine-immune could focus more on the complex acupuncture manipu- network. lation parameter combinations. In studies of the dose–effect relationship of acupunc- ture, it is difficult to define the minimal acupuncture “dosage”. The de qi response offers a solution to this De qi response conundrum, because it can reflect the minimal acupunc- In the traditional Chinese medicine theory system, qi is ture stimulation dosage to evoke a therapeutic effect. In the fundamental material of the human body, providing a comparison of a group receiving standard Xingnao energy for functional activity. Interventions from out- Kaiqiao acupuncture therapy and showing the de qi side, such as acupuncture, exert effects by regulating the response to a similar acupuncture group without a de disordered state of qi. De qi is a classic term in tradi- qi response, a previous study found different functional tional Chinese medicine, representing adequate acupunc- connectivity characteristics in the motor area of post- ture stimulation. A de qi response is a manifestation of  stroke patients . A systematic review that used the de qi qi regulation and is presented as an intensified sensation response as the standard for acupuncture dosage found in some acupuncture treatments, such as body acupunc- that a higher acupuncture dosage was related to bet-  ture . It should also be noted that in other acupuncture  ter clinical outcomes in KOA patients . Therefore, the therapies, such as abdominal needling, floating needling, de qi response is an important standard for measuring and wrist and ankle needling, a de qi response can pres- whether the effect is adequate for the treatment demand.  ent as no sensation . The de qi response includes the However, the de qi response is a qualitative description. response of patients after receiving acupuncture, and To evaluate the de qi response accurately, and to analyze the sensation of the acupuncturist after conducting the the co-relationship among de qi response, acupuncture acupuncture operation. Generally speaking, the de qi dosage, and treatment effect, there is a need for an instru- response refers to the patient’s subjective feelings after ment for evaluating the de qi response. Currently, vari- receiving acupuncture, such as experiencing aching, ous assessment scales for the de qi response are applied, numbness, dullness, heaviness, radiating, and spreading which include the Southampton Needling Sensation feelings. The various de qi responses are induced via dif- Questionnaire, the Acupuncture Sensation Scale, the ferent mechanism pathways. Massachusetts General Hospital Acupuncture Sensation The de qi response is induced by stimulating the skin  Scale, and the Subjective Acupuncture Sensation Scale , and subcutaneous tissue using different acupuncture which provide a visualized alternation for further study.  manipulations , it affects the acupuncture effect in the following four aspects. First, the local initial effect of acu- Nonspecific factors influencing the dose–effect relationship point: After needle penetration, the manipulation of the needle body reinforces the stimulation of the needle tip Comparison selection on connective tissue, vascular tissue, nervous tissue, and muscular tissue around the acupoint area. Different de The control group should be chosen to reveal the real qi sensations are evoked by needle tip stimulation on dif- effects of different acupuncture dosages; thus, other inter- ferent tissues, which triggers different sensory receptors, ventions should be consistent with those of the treatment such as muscle spindles, tendon organs, free nerve end- group, except for the acupuncture dosage. In studies of  ings, joint capsules, and Pacinian corpuscles . Second, the acupuncture dose–effect relationship, the compari- the signal conduction effect: The activated receptors son should therefore depend on different acupuncture transform acupuncture mechanical stimulation into an dosages. There are two mainstays of the comparison electrical signal, which is conducted by different afferent set, one is the comparison of different acupuncture fibers, including Aδ fibers, Aβ fibers, and C fibers, result- dosages, and another is the comparison between a cer-  ing in the de qi sensations in the cerebral cortex . The tain acupuncture dosage and the placebo acupuncture  central neural integration effect is the third part, which or no treatment (including the waiting list) . For the generates different de qi sensations. For instance, tak- former type, the variables of control groups can include ing advantage of neuroimaging technology, functional single or multiple acupuncture manipulation parame- magnetic resonance imaging examination revealed that ters as we mentioned in the Acupuncture manipulation there was a significant difference in the eigenvector cen- parameters section. While for the latter, the stimulation trality between participants who received acupuncture type and stimulation dosage of placebo acupuncture  with or without de qi response . During acupuncture, are vital factors influencing the dose–effect relationship. intensified manipulation of the needle strengthens the According to clinical studies and systematic review anal- mechanical stimulation, influencing the metabolism of ysis, the effective power of acupuncture varied when it + 2+ + K , Ca , and Na and the release of 5-hydroxytrypto- was compared with different comparisons such as no  phan, substance P, and histamine around the acupoint . treatment group/waiting list group, sham acupuncture, These active factors have an impact on the neuro-en- and different types of sham acupuncture (non-pene- docrine-immune network, which provides the struc- trating needling, superficial needling, and deep needling   tural and functional basis for acupuncture effect . at non-acupoints) . An improper comparison with 224 Li et al. • Volume 2 • Number 4 • 2022 www.ahmedjournal.com a therapeutic effect might cover the real effect of acu- acupuncturists with greater practice experience who can puncture, and affect the conclusion in the study of the conduct a better manipulation in acupuncture and sham dose–effect relationship. Hence, the control intervention acupuncture operations. For the outcome selection, the should be considered cautiously. objective index is recommended since it can be less likely  influenced by the placebo effects . Blinding procedure Patient’s expectancy Several studies have demonstrated the placebo effects of acupuncture operation, particularly in analgesia stud- Patient expectancy is one of the nonspecific factors influ-  ies . However, evidence-based studies have validated that encing the acupuncture effect, it refers to the anticipation acupuncture has superior effects as compared to sham of patients about their treatment, response, outcome, and [48–49]  acupuncture , declaring that the acupuncture effects other reactions during the trial . It is affected by the cannot be explained simply by placebo effects. Using a patient’s treatment experience, the interaction between blinding procedure is a powerful way to reduce bias arising the patient and clinician, and the subjective perception  from the co-intervention of clinicians and participants, and of the patient during the trial . According to a litera-  to minimize placebo effects . Given the potential placebo ture study, there are two prototypical types of patient  effects, which might amplify the real effects of acupunc- expectancy . “Outcome expectations” reflect patients’ ture, the introduction of an appropriate blinding procedure prognostic feelings about the therapeutic effects, and is indispensable. Particularly, in a study of the acupuncture “Treatment expectations” suggest patients’ personal dose–effect relationship, the use of an improper blinding beliefs about their interaction with the therapist, their procedure might cause exaggerated effects, leading to inac- feeling after receiving the treatment, the treatment dura- [57–58] curate optimal dosage parameters. Due to the operational tion, and treatment consistency . characteristics of acupuncture, it is difficult to blind the A high-level positive expectancy might cause a pla- acupuncturist. Thus, the blinding procedure only relates to cebo effect, while a negative expectancy, such as fear,  the participants, the outcome assessor, the data manager, might inhibit the analgesic effect of acupuncture . and the statistician. Among these, the blinding of the par- Given the interaction between acupuncturists and ticipant is the basis of the blinding procedure. patients, a positive expectancy might amplify the ther-  Currently, there are three types of sham acupuncture apeutic effects . On the other hand, some research used in blinding the participants. In terms of the needle presented the opposite conclusion, indicating that the type, a non-penetration needle is applied to simulate the treatment outcomes were inconsistent with patients’  acupuncture procedure. For example, both the classic preferences for acupuncture . Therefore, in the study Streitberger needle and the Park sham device contain a of the acupuncture dose–effect relationship, the homo- pad between the skin and the needle as well as a blunt geneity of outcome expectations and treatment expec- [50–51] needle tip, which prevents needle penetration . For tations among groups might cause expectation effects. acupuncture manipulation, one alternative is superficial To solve this problem, one practicable way is to take acupuncture. It maintains similarity to the acupuncture the expectation degree as a stratification factor in ran- procedure, except for the needle depth. To reduce oper- domization. By balancing patient’s baseline character- ation bias, a depth of 2 to 5 mm, which is above the istics, the outcome expectation effects can be reduced. muscular tissue, is typically used as the superficial acu- Another way is to minimize the treatment expectations,  puncture depth . For acupoint selection, non-acupoints which requires the therapist to maintain uniformity in and non-meridian points without therapeutic effects are the acupuncture operation and communication with practicable approaches. This approach is highly consis- participants during the trial. tent with true acupuncture in the needling procedure, and the penetration operation is acceptable for patients. Ethics and compensatory acupuncture In the acupuncture dose–effect relationship study, the above blinding procedures can be used to accomplish In a clinical study, ethical approval is a guarantee of blinding of the participant, but not that of the acu- the safety of and benefits to participants. Considering puncturist. Recently, auxiliary devices have provided the study of the acupuncture dose–effect relationship, approaches for double-blinding (both participant and participants in groups of different acupuncture dosages acupuncturist). Using electroacupuncture, block of the might obtain different therapeutic effects; thus, compen-  current is a practical way to achieve double-blinding . satory treatment is necessary. Currently, compensatory To ensure a blinding procedure, the combination of treatment includes acupuncture treatment, conventional  several procedures can be used, such as the non-pene- treatment, or standard treatment . For the study of tration at non-acupoints with current-block electroacu- the acupuncture dose–effect relationship, compensatory  puncture . Moreover, to minimize the placebo effects, treatment can be acupuncture therapy at the optimal during the acupuncture operation, the acupuncturist therapeutic effect parameters. The time point of com- could reduce interaction with participants. Meanwhile, pensatory treatment starts after the observation period in the dose–effect relationship study, participants in of intervention or the follow-up stage. Another feasible different groups receive acupuncture with different way to protect participants’ benefits is to provide health-  manipulation parameters, causing various needle senses care or give health education . To reduce bias rising in participants. Given the difficulty of performing the from different interventions among groups, conventional blinding procedure in participants who are with acu- treatment, standard treatment, or education treatment puncture treatment experience, it is necessary to select should maintain consistency throughout the trial. 225 Li et al. • Volume 2 • Number 4 • 2022 www.ahmedjournal.com Discussion and the body. Recent studies have illustrated the possible mechanism underlying the acupuncture dose–effect rela- The acupuncture dose–effect relationship is a complex tionship in terms of neural electrophysiology and neu- research question, for both “dose” and “effect” are asso-  ro-endocrine pathways . However, most studies of the ciated with multiple factors. In this article, we summa- effect mechanistic pathways of acupuncture remain in a rized the vital methodological strategies in studies of preliminary stage, and further systematic investigations the acupuncture dose–effect relationship. By analyzing are required. factors that influence acupuncture dosage and effect, we Additionally, this review had some limitations. First, offered practical suggestions according to current issues. this study analyzed the core challenges and offered Considering different research objectives and study advice in terms of acupuncture dose–effect study design, procedures, we have offered advice for studies of the but other aspects of trial design, such as randomization, dose–effect relationship of single acupoints and acupoint sample size estimation, and outcome selection are not combinations. Our suggestions might facilitate the design fully illustrated. The methodological problems were of future studies on acupuncture dosage and effect, and selected according to the existing puzzles of acupunc- may establish a methodological system for evaluating ture dose–effect studies. Since the methodological system the acupuncture dose–effect relationship. In addition, for studying acupuncture dose–effect relationships is in clarification of a specific “dose” has great significance in a preliminary stage, further studies could consider inte- acupuncture treatment, as it is not only associated with grating such a system. Second, this study mainly focused the evaluation of therapeutic effect, but also influences  on a RCT design and experimental research. For design health economics . In some chronic diseases, such as of trials of the acupuncture dose–effect relationship in musculoskeletal pain, a sufficient treatment course is  other study types, further exploration is required. Third, required to achieve therapeutic effect . Patients with although the research topic in this review was acupunc- insurance benefits are more likely to complete the full ture treatment, the dose–effect relationship should also course of acupuncture treatment. With the expansion  be investigated in other traditional Chinese medicine of health insurance , the optimal dosage needs to be  external therapies, such as moxibustion. Considering defined to provide the basis for policymaking . that both acupuncture and moxibustion play a role by Current evidence has proven that this relationship applying external stimulation to the body, the stimulat- between acupuncture dosage and effect is not a simple ing dosage is a core factor influencing therapeutic effect. linear relationship. Besides methodological problems A recent study has proven the dose-dependent effect in in study design, how to define the dosage and effects  moxibustion therapy , but further studies should high- qualitatively is an unavoidable challenge. Recently, the light the significance of the dose–effect relationship in combination of multidisciplinary fields has provided these therapies. modern technological support. In the modern medicine system, acupuncture technology is considered an extra-  neous mechanical stimulation . Through needle stimu- Conclusion lation, acupuncture evokes electroneurographic signals The acupuncture dose–effect relationship is a complex and induces exciting conduction. Neural pathways have research question that involves various factors. To date, been proven to be crucially involved in the mechanism studies have proven that acupoint selection, needle [68–69] underlying the effects of acupuncture . Based on these depth, needle twirling frequency, needle direction, needle mechanisms, researchers who focus on the manipulation retention time, and treatment sessions can influence acu- of acupuncture have proposed the hypothesis of the con- puncture effects. However, acupuncture therapy is com-  nective tissue pathway , which proposes that, after per- plicated, and the mechanism underlying its dose–effect forming acupuncture manipulation, such as twirling, the relationship is not yet fully illustrated. Taking advantage needle tip is entwined in the connective tissue beneath the of modern technology, further studies can explore the acupoint. Reinforcement of acupuncture manipulation mechanistic pathways of this relationship. results in the deformation of collagenous fibers, evoking Our perspectives offer insight into the factors related the mechanical signaling pathway that is conducted via to acupuncture dosage and effect, including specific [71–72] the fascia network . Combining advanced technol- influencing factors (acupoint selection, acupuncture ogy of biology and mechanics, an acupuncture param- manipulation parameters, de qi response) and nonspe- eter collection system is applied in manipulation studies, cific influencing factors (comparison selection, blinding which records and analyzes the manipulation parameter procedure, patient’s expectancy). Further studies need to characteristics. In this way, the acupuncture manipulation be conducted to establish a methodological system and can be recorded as quantified data, providing the possi- to provide systematic evidence on the acupuncture dose– bility of accomplishing an acupuncture network system effect relationship. in terms of the acupuncture dose–effect level. Multiple evidence-based studies have validated that the dose–effect relationship of acupuncture alters the thera- Conflict of interest statement peutic effects of acupuncture and the mechanistic path- The authors declare no conflict of interest. ways, providing the basis for an acupuncture dose–effect relationship. Using experimental research, the dose– Funding effect relationship of acupuncture has been revealed on different levels, such as the mechanism of acupoint acti- This research was funded by the Ministry of Science and vation, and conduction between the acupoint, meridian, T echnology of the People’ s Republic of China, National Key 226 Li et al. • Volume 2 • Number 4 • 2022 www.ahmedjournal.com  Zhang YQ, Jiao RM, Witt CM, et al. How to design high qual- Research and Development Program (2010CB530506, ity acupuncture trials—a consensus informed by evidence. BMJ 2018YFC1706001, 2019YFC0840709); Tianjin 2022;376:e067476. 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Acupuncture & Herbal Medicine – Wolters Kluwer Health
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