Severe discomfort due to strong gag reflexes and pain during upper gastrointestinal endoscopy (UGE) often results in a stressful experience for patients who undergo the procedure and occasionally hinders the success of the procedure (1, 2). As a result, sedated UGE procedures with less discomfort and pain have been the predominant method used in endoscopic clinics in Europe and North America (3, 4). However, there are concerns regarding the cost and adverse events (e.g., cardiopulmonary events, allergic reactions) associated with the use of sedatives for UGE, especially in the elderly population with pre-existing cardiopulmonary disease (5, 6). Therefore, unsedated UGE is still being used by many physicians and patients in China and other developing countries (7, 8). Topical pharyngeal anesthesia (TPA), which has been reported to be effective in suppressing the threshold of the gag reflex, is often applied before an unsedated UGE to ease discomfort and pain (9–11). However, involuntary gagging cannot be suppressed among certain patients even after the use of TPA due to sensitive gag reflexes (9).

Acupuncture is a therapeutic intervention that involves the insertion of fine needles into the skin or deeper tissues at specific locations on the surface of the body with the aim of curing disease or promoting health, according to the theory of Traditional Chinese Medicine (12). Acupuncture has been frequently used to treat various diseases including nausea and vomiting associated with chemotherapy, pregnancy, and recovery from surgical procedures (13, 14), and some published studies have also demonstrated that acupuncture may be able to increase tolerance and reduce discomfort during UGE (15, 16). A systematic review in 2004 on the effect of acupuncture during gastrointestinal (GI) endoscopies included only six studies with inconclusive findings. However, it did not distinguish UGEs from colonoscopies, nor sedated from unsedated procedures, during which the patient status would be very different (17). On the other hand, the number of studies focusing on acupuncture to relieve patient discomfort during an unsedated UGE has increased, and many have reported that acupuncture was often used in conjunction with TPA during an unsedated UGE. However, there have been no systematic reviews concerning the effect of acupuncture on discomfort during UGE since 2004. Therefore, the current systematic review and meta-analysis was conducted with the aim of evaluating current evidence on acupuncture for the management of discomfort during an unsedated UGE, and thus providing up-to-date recommendations for clinical practice and decision-making.

This systematic review and meta-analysis were conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) (18). The protocol was registered at PROSPERO with registration number CRD42014008966 (19).

A total of 2,462 studies were identified through an initial search. After removing duplicates, 1,939 studies were reviewed by title and abstract, and 1,756 studies were excluded for not meeting the inclusion criteria. Next, the full-text of 175 studies were obtained for further assessment, and 23 studies were considered eligible for the review according to the inclusion and exclusion criteria, and four studies were included in the meta-analysis. The details of the study selection process were shown in a PRISMA flow diagram (Figure 1).

To the best of our knowledge, this is the first systematic review and meta-analysis to assess the effect of acupuncture on the improvement of discomfort during UGE procedures. Among the 23 included RCTs, the results (improvement of VAS or INV) were in favor of acupuncture plus TPA (primarily TPALH) compared with TPA alone, among studies of MA, EA, AP, SFN, and acupressure. However, the results appeared inconsistent when comparing acupuncture methods alone to anesthetics, sham acupuncture, usual care, or no treatment. Most of the included studies did not report any adverse events in their findings and were of medium-to-high risk of bias.

Some studies explored the anti-emetic effects of acupuncture that might be associated with an increase in the hypophyseal secretion of beta-endorphins and adrenocorticotropic hormone, together with subsequent suppression of the chemoreceptor trigger zone and vomiting center (43, 44). Studies have shown that the Neiguan (PC-6) acupoint, which is the most commonly used acupoint to treat GI symptoms, may reduce nausea through a variety of mechanisms, including neurotransmitters (e.g., the endogenous opioid system, serotonin transmission), a direct influence on the smooth muscle of the gut, somatovisceral reflex, sensory input inhibition, somatosympathetic reflex-induced gastric relaxation, vagal modulation, central cerebellar modulation, or psychological aspects (45, 46). Some studies have indicated that Zusanli (ST-36) and Neiguan (PC-6) have a synergistic effect on gastric myoelectrical activity (47, 48). However, the true mechanism by which acupuncture relieves discomfort during UGE remains inconclusive.

An early systematic review (2004) (17) on discomfort during GI endoscopy (including UGE and colonoscopy) with six RCTs found that the effect of acupuncture (EA and MA) on relieving discomfort was similar to active medication, but better than that of sham acupuncture, with or without TPA or a sedative (17). The results described in the current review suggest that regardless of the type of acupuncture, the VAS score of discomfort during UGE in groups with acupuncture plus TPA was significantly lower than of TPA-alone, which was not claimed in the previous review. These results could indicate that the use of acupuncture as an adjuvant therapy could enhance the effect of TPA and thus may reduce the amount of TPA required during UGE. When comparing EA or MA with sham acupuncture, the results in the current review were inconsistent across studies with or without TPA, which diverged from the conclusions of the previous study (17).

It was unfortunate that we did not find substantiative evidence regarding the minimum clinical important difference of the VAS scores of discomfort (one of the major measurements of discomfort) during GI endoscopy from previous studies and systematic reviews (17). The discomfort during UGE and colonoscopy procedures is often regarded as comparable due to one common mechanism - the pressure of air distension (49). One previous study reported that the VAS pain scores during a colonoscopy were significantly lower in patients receiving anesthetics plus acupuncture (1.4 ± 0.4) compared to patients receiving anesthetics plus sham acupuncture (3.0 ± 0.3), with a difference of −1.30 (−1.58, −1.02, P = 0.003) (50). Another study reported the VAS discomfort scores in EA and SA groups were significantly different at 24 mmHg (pressure of air distension) during a colonoscope (2.80 vs. 4.74, P = 0.013) (51). In the current review, the mean VAS scores of discomfort ranged from 2.94 to 4.80 after treatment in patients receiving TPA plus acupuncture, and from 3.94 to 6.3 in patients receiving TPA only, with MD ranging from −1.11 to −0.65 (P all <0.05). Although the data of the VAS scores presented above looks comparable across studies, it would be arbitrary to draw any conclusion with the limited data and substantial heterogeneity regarding type of acupuncture, regimens (including beginning and ending time of acupuncture treatment in relation to the endoscopy, the total duration of endoscopy, acupoints selected, intensity of simulation), skills of doctors, as well as level of risk of bias.

It is worth mentioning that the outcome measurements used by the studies included in this review varied considerably, which hindered the syntheses of effects across all studies. For instance, considering the level of discomfort, nearly half of the included studies did not use internationally recognized tools, such as VAS or NRS, to measure the level of discomfort. Instead, they developed a ranking system to categorize the effect of acupuncture without a consistent definition for each rank across multiple studies. In addition, numerous factors can influence the discomfort level during a UGE procedure, such as the size of endoscopy lens, physical sensitivity and characteristics of the patients (e.g., age, sex, tolerance, upper gastrointestinal diseases, and previous endoscopy experience), time of measurement, the UGE operator's experience (52), etc. However, limited information was reported on the above factors to allow for further understanding or analysis on the effect of acupuncture. Given the side effect of TPA or sedatives, a reduced dosage when combined with acupuncture should be another key reflection of the effect of acupuncture. However, not all studies reported on this outcome (28, 35). None of the studies reported any data on cost-effectiveness of the use of acupuncture during UGE.

The current review has many strengths. It included a greater number of studies than the previous review, focused specifically on unsedated UGE, and used a comprehensive search of both English and Chinese language biomedical databases. However, several limitations are also present. Firstly, the 23 RCTs were heterogeneous regarding the type and regimen of acupuncture and the control group, as well as outcome measurements, which limited our attempt to synthesize the effect from individual studies (Figure 6). Secondly, the tolerance of discomfort and acceptance of sedated UGE vary considerably among patients in different countries. More than 90% (21/23) of the included studies were conducted in Asian countries (i.e., China, Turkey), and only two were carried out in Europe (i.e., France, Germany), which may constrain the generalization of the results. Thirdly, with limited information, the review was not able to determine the specific characteristics of patients (e.g., sex, age) may benefit more from acupuncture, and which type of acupuncture and stimulation were superior to others. Fourthly, due to the lauguage capacity, we didnot search Korean or Japanese databases specially, which might add publication bias out of regional inequality.

In this review, it was shown that acupuncture, as an adjuvant therapy to TPA, may further decrease discomfort levels compared to TPA alone. When compared with sham acupuncture, usual care, or no treatment, the effect of acupuncture was not consistent. Findings from this review should be interpreted with caution given the heterogeneity and bias identified across the studies. Rigorously designed RCTs that measure standardized and clinically relevant outcomes are needed to inform clinical decision-making regarding the use of acupuncture for discomfort relief during unsedated UGE procedures.

The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author/s.

WW and ZL contributed to study conception and design. NG and HC searched the databases, reviewed studies, and assessed the quality of studies. YW and YG analyzed data and carried out the statistical analysis. This manuscript was drafted by NG and revised by WW and HC. All authors approved the final version of the manuscript.

This study was funded by the China Academy of Chinese Medical Sciences (Grant No. ZZ13-YQ-019). The funding agency had no role in the design or conduct of the study.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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