The Effectiveness of Acupuncture in Prevention and Treatment of Postoperative Nausea and Vomiting - A Systematic Review and Meta-Analysis

Background Acupuncture therapy for preventive and treatment of postoperative nausea and vomiting(PONV), a condition which commonly present after anaesthesia and surgery is a subject of growing interest. Objective This paper included a systematic review and meta-analysis on the effect of different type of acupuncture and acupoint selection in PONV prevention and treatment. Methods Randomised controlled trials(RCTs) comparing acupuncture with non-acupuncture treatment were identified from databases PubMed, Cochrane, EBSCO, Ovid, CNKI and Wanfangdata. Meta-analysis on eligible studies was performed using fixed-effects model with RevMan 5.2. Results were expressed as RR for dichotomous data, with 95%CI. Results Thirty RCTs, 1276 patients (intervention) and 1258 patients (control) were identified. Meta-analysis showed that PC6 acupuncture significantly reduced the number of cases of early vomiting (postoperative 0-6h) (RR=0.36, 95%CI 0.19,0.71; P=0.003) and nausea (postoperative 0-24h) (RR=0.25, 95%CI 0.10,0.61; P=0.002), but not early nausea (postoperative 0-6h) (RR=0.64, 95%CI 0.34,1.19; P=0.150) and vomiting (postoperative 0-24h) (RR=0.82, 95%CI 0.48,1.38; P=0.450). PC6 acupressure significantly reduced the number of cases of nausea (RR=0.71, 95%CI 0.57,0.87; P=0.001) and vomiting (RR=0.62, 95%CI 0.49,0.80; P=0.000) at postoperative 0-24h. PC6 electro-acupoint stimulation significantly reduced the number of cases of nausea (RR=0.49, 95%CI 0.38,0.63; P<0.000) and vomiting (RR=0.50, 95%CI 0.36,0.70; P<0.000) at postoperative 0-24h. Stimulation of PC6 with other acupoint(s) significantly reduced the number of cases of nausea and vomiting (RR=0.29, 95%CI 0.17,0.49; P<0.000) at postoperative 0-24h. Stimulation of other acupoint(s)(non PC6) also significantly reduced the number of cases of nausea and vomiting (RR=0.63, 95%CI 0.49,0.81; P=0.000) at postoperative 0-24h. However, the quality of study was generally low in studies of PC6 combined with other acupoint(s) and other acupoint(s). Details of blinding were not reported in most reports. Conclusions Besides PC6, PC6 combined with other acupoint(s) and other alternative acupoint(s) might be beneficial in prevention and treatment of PONV, the evidence justifies future high-quality studies.


Introduction
Postoperative nausea and vomiting (PONV) is a condition commonly present after anaesthesia and surgery, with overall incidence of 40%-90% [1]. Despite the use of newer drugs, PONV within 24 hours still occurs in 25%-30% of patients [2].
Though self-limitating, PONV can cause significant morbidity including dehydration, electrolyte imbalance, suture tension and dehiscence, venous hypertension and bleeding, esophageal rupture, and life-threatening airway compromise, although the more severe complications are rare [3]. PONV increases medical cost. An episode of vomiting could prolong postanaesthetic care unit (PACU) stay by about 25min [4].
Type of anaesthesia, type of surgery and site of operation contribute to PONV occurrence rate. Breast and gynaecological surgeries presented the most frequent report of PONV in adults [1]. Operations associated with high incidence of vomiting in children include strabismus, adenotonsillectomy, hernia repair, orchidopexy and penile surgery [4]. Research also demonstrated higher PONV occurrence rate in patients under general anaesthesia [5].
Limited efficacy and side effects with antiemetics led to the use of alternative treatment [1]. Researches in various countries believe acupuncture improves the quality of patients' life [2]. An inventory concerning 32,000 acupuncture consultations in UK revealed the most common adverse events of bleeding, needle pain and aggravation of symptoms, but none were serious [1]. Various type of acupuncture has been used in mainland China and abroad [2], but the most suitable method is yet to be confirmed.
According to the theory of traditional Chinese medicine (TCM), surgery breaks the balanced state of the human body and disturbs the movement of both qi and blood [6], causes the stomach qi to reverse its direction and go upward, causing nausea and vomiting [6]. One of the PC6's functions is to avoid the adverse flow of qi, thus is an effective acupoint in preventing nausea and vomiting [6].
Researchers gradually realised that PC6 may not be the only acupoint in PONV treatment [8]. Patients' diseases and specific symptoms should be considered for method of selection [8].
The timing of acupuncture intervenes has also been an argument. Dundee JW and Ghaly RG (1989) [10] demonstrated a significant reduction in PONV incidence following preoperative PC6 acupuncture. However, Weightman WM et al. (1987) [11], did not find similar effect in their studies. The former [10] gave a possible explanation in terms of the timing of acupuncture intervene. To be effective, it should be administrated before the emetic stimulus. Yang LC et al. (1993) [12], however, found that PC6 electro-acupuncture administered in the recovery room was effective in reducing postoperative emesis.
This study is carried out to evaluate the efficacy of different type of acupuncture, acupoint selection, optimal timing, technique of intervention, side effects and used of rescue therapy in PONV in the recent years.

Materials and Methods
A research protocol was drafted and approved by the faculty members. A copy was kept by the principal investigator.
Quality of studies was assessed using GRADE profiler version 3.6. Items evaluated included: All trials were evaluated using CONSORT [14] and STRICTA [15] for TCM according to the standard guideline. Items evaluated included title and abstract, introduction, methods, discussion and other information for CONSORT; acupuncture rationale, details of needling, treatment regimen, other components of treatment, practitioner background and control or comparator interventions for STRICTA.
One study on PC6 [20] and 1 on other acupoint(s) [41] were based on paediatric population while the remaining were on adults.
Type of acupuncture and acupoint selection Funnel plot were shown in Figure 10.
For other acupoint(s), in 1 study, cupping therapy was applied for 10min at postoperative 6h and 24h [38]; in another study electro-acupuncture was performed for 25min, followed by acupoint injection bd [39]; in a study, auricular acupressure was performed for 1-3min for 2-3 times during surgery, followed by 3-4 times daily post-surgery [41]; in 1 study acupoint massage was performed for 10-15min every 4-6h [44]; and in another study auricular acupuncture was applied every 30min and kept until end of surgery [45].

Side effects
Of the 30 studies, 10(33.33%) reported no side effects. One study(3.33%) with acupressure wristbands and sham, reported redness, swelling, tenderness and paraesthesia of wrist and hand in approximately 1/3 of patients. The local side effects caused by the acupressure wristband were equally distributed between PC6 stimulation and sham [25]. Another study with acupressure band reported swelling and erythema of the treated hand, where patient finally excluded from the study [26]. A study on electro-acupuncture reported local complication of erythema in 15% of cases [27]. Two studies(6.67%) reported no major side effects [23,37]. The remaining 15(50.00%) studies did not report whether there were any side effects in their findings.
Subset analysis by gender in 1 study [24] with Dimenhydrinate 50mg i/v showed that acupressure group female patients required less antiemetic than control. However, no significant difference was noted in male patients.
Moderate quality of evidence was mainly due to precision not reported in the study outcomes while low quality of evidence was due to study not blinded and precision not reported in the study outcomes.   For prevention of nausea (postoperative 0-24h), PC6 acupuncture vs. no acupuncture had the lowest pooled RR, followed by PC6 electro-acupoint stimulation vs. sham and PC6 acupressure vs. sham. PC6 acupuncture vs. no acupuncture seemed to be most effective amongst the three groups, followed by PC6 electro-acupoint stimulation and PC6 acupressure vs. sham.
For prevention of vomiting (postoperative 0-24h), PC6 electro-acupoint stimulation vs. sham had the lowest pooled RR, followed by PC6 acupressure vs. sham and PC6 acupuncture vs. no acupuncture. PC6 electro-acupoint stimulation vs. sham seemed to be most effective amongst the 3 groups, followed by PC6 acupressure vs. sham and PC6 acupuncture vs. no acupuncture.
Overall, all modalities seemed to be effective in PONV prevention. Electrical stimulation with ReliefBand or electrodes might be more costly than manual needling, however it is reusable and more effective in some cases. ReliefBand and electrode were less invasive, require minimal training and cost-  local effects such as swelling, erythema [25,26], tenderness or paraesthesia [25] had been reported in few studies with ReliefBand.
Meta-analysis by Shiao SY, Dibble SL 2006 found that acupressure was more effective in reducing symptoms for adults (pregnant or postoperative) than children, and is as effective and more feasible to use than medications and acupuncture modalities [7]. Study by El-Bandrawy AM et al 2013 showed a significant decrease in nausea and vomiting in patients treated by acupressure in addition to anti-emetic drug; while PC6 TEAS was more effective than acupressure in alleviating PONV after abdominal hysterectomy [46]. Acupoint PC-6. For PC6 acupuncture vs. no acupuncture, stimulation of PC6 significantly reduced the number of cases of early vomiting (postoperative 0-6h) and nausea (postoperative 0-24h). However, it seemed not effective for early nausea (postoperative 0-6h) and vomiting (postoperative 0-24h). At postoperative 0-24h, both PC6 acupressure and PC6 electroacupoint stimulation vs. sham significantly reduced the number of cases of nausea and number of cases of vomiting. Study by Streitberger K et al 2004 [47] on PC6 acupuncture in women undergoing gynaecology and breast surgery showed that differences in incidence of PONV and/or use of anti-emetic rescue were more pronounced in patients having gynaecological surgery (48.9% acupuncture, 67.6% placebo, P=0.07) than breast surgery (38.7% acupuncture, 40.3% placebo, P=0.86). Author concluded acupuncture at PC6 might be effective in patients having gynaecological surgery, but not in patients having breast surgery.
In a study by Majholm B and Møller AM, 2011 [25] using PC6 acupressure vs. sham, no statistical significance was noted for incidence of nausea or vomiting between the treatment and control group in women undergoing breast surgery.
PC6 intervention is simple, inexpensive, and noninvasive with minimal side effects. However, there were limitations with PC6 alone. For example, stimulation of PC6 in eye and breast surgery might not be effective. PC6 combined with other acupoint(s) and use of alternative acupoint(s), such as auricular acupuncture, cupping therapy, catgut embedment, might provide better prospect for prevention and treatment in PONV.

P6 combined with other acupoint(s).
Meta-analysis showed that stimulation of PC6 combined with other acupoint(s) significantly reduced the number of cases of PONV compared to control group at postoperative 0-24h.
Stimulation of PC6 combined with other acupoint(s) at postoperative 0-24h had lower pooled RR compared to other acupoint(s) and seemed more effective than the latter. However, the efficacy in prevention of nausea or vomiting alone could not be evaluated due to lack of studies in the former group.
Common acupoints used were ST36 (Zusanli), LI10 (Shousanli) and LI4 (Hegu). ST36 is located along the Stomach Meridian of Foot-Yangming, which function in adjusting qi and blood, food transport and gastrointestinal activity. After surgery it helps to stimulate the relaxation of gastrointestinal contractions, and enhance body resistance. PC6 is located along the Pericardium Meridian of Hand-Jueyin. Stimulation of PC6 help to adjust the endocrine function, release of epinephrine and vasopressin, inhibit gastic acid secretion, regulate gastrointestinal motility, relieve stomach cramps, and has better effect on sympathetic vomiting and anaesthesiainduced nausea and vomiting. Stimulation of PC6 and ST36 produced better and strengthened anti-emesis effect.
Early stimulation of LI10 and ST36 is effective in PONV prevention and treatment in abdominal surgery. Stimulation of ST36 strengthens and helps to regulate the function of spleen and stomach digestion, smooth and clear the function of qi and blood. LI10 is an important acupoint of the Large Intestine Meridian of Hand-Yangming, and directly connected with the large intestine. It is beneficial in the regulation of the flow of qi and blood of the organs and postoperative symptoms of abdominal surgery.
LI4 is located along the Large Intestine Meridian of Hand-Yangming. With combination with ST36, it helps to regulate the stomach to function more smoothly. Stimulation of LI4, PC6 and ST36 effectively inhibit the vagus nerve which helps to stabilise the cardiovascular function, improve anaesthetic effect, enhance analgesia, adjust the autonomic functions of the digestive system, promote gastrointestinal peristalsis and facilitates patients' recovery.
Study by Yu JM et al 2010 [32] on the effect of TEAS on breast radical carcinoma surgery showed that stimulation of LI4 with PC8 and PC6 with TE5 significantly reduced the need of analgesia and number of cases of PONV compared to control (under general analgesia only). It has been demonstrated that acupuncture produces analgesia via the body endorphin system which could be antagonized by naloxone [48]. The analgesic effect of TEAS may be related to its effect in upregulating plasma beta-endorphin level [32].
Other acupoint(s). Meta-analysis showed that stimulation of other acupoint(s) significantly reduced the number of cases of nausea and/or vomiting in patients at postoperative 0-24h.
Lu ZX et al 2009 [38] used cupping therapy for PONV prevention among patients undergoing laparoscopy cholecystectomy. Cupping was applied at the patients' back which consists of Du Mai (GV-, governing vessel) and the Kidney Meridian which helps to regulate the flow of blood and qi to become more smoothly and helps to balance yin and yang. Yang W et al 2011 [40] performed a preoperational catgut implantation at bilateral BL57 on patients undergoing hemorrhoid operation, and found to be significantly more effective than medication in reducing pain, nausea and vomiting.
Stimulation at acupoints such as large Intestine LI4 (on the hand), Spleen SP6 (on the lower limb), and "back-shu" (paravertebral area) have been shown to have analgesic properties [49].
Auricular acupoint application was found to be effective in reducing pain [42], nausea and vomiting [41,42,45], in adult [42,45] and children [41]. Auricular acupuncture reduced the concentration of 5-HT, which is the main cause of vomiting by acting on the peripheral nerve plexus of the small intestine of the receptor that mediate vomiting [45].  [22] found that Korean Hand acupressure on K-K9 (located at middle phalanx of the 4th finger, corresponds to PC6) was effective for reducing PONV in women after minor gynecological laparoscopic surgery.

Optimal time and technique of intervention
Timing of intervention. Previous meta-analysis indicated that the antiemetic effect of acupuncture require treatment of awake rather than anesthetized patients [51]. Study by White PF et al 2005[52] to deduce the optimal timing of acustimulation for patients undergoing plastic surgery found that perioperative use of ReliefBand (applied for 30min before and 72h after surgery) significantly increased the complete responses (68%) compared to before surgery only (43%) (applied for 30 min before surgery). Median postoperative nausea scores were significantly reduced and patient satisfaction (with quality of recovery and antiemetic management) was significantly higher in the former group. For patients discharged on the day of surgery, time to home readiness was significantly reduced when acustimulation was administered perioperatively (vs. preoperatively). Acustimulation with ReliefBand was most effective in reducing PONV and improving patients' satisfaction with their antiemetic therapy when it was administered after surgery [52].
Systematic review by Holmér Pettersson P and Wengström Y 2012 [1] found that acupuncture prior to surgery reduced the incidence of nausea but not vomiting compared to antiemetic prophylaxis alone.
Yentis SM and Vashisht S 1998 [53] performed a study on whether antiemetic effect of PC6 acupuncture in preventing PONV is affected by the timing of administration in 50 patients undergoing major gynaecological surgery. Patients were randomly assigned to receive PC6 acupuncture either 5 min before induction of anaesthesia (Group 1), 5 min after induction of anaesthesia (Group 2) or when awake in recovery room post-operatively (Group 3). Results showed no significant differences in the emetic sequelae amongst the three groups, with incidence of vomiting of 29%, 24% and 25% within the first 6h post-operatively. General anaesthesia does not affect the antiemetic action of PC6 acupuncture.
Lee A and Done ML [54] showed that non-pharmacologic techniques (acupuncture, electro-acupuncture, TEAS, acupoint stimulation and acupressure) were more effective than placebo in preventing nausea and vomiting within 6h of surgery in adults, but not in children. Study by El-Bandrawy AM et al 2013 showed that time was an important variable, with significant effects of acupressure in the first 6 h [46].
It has been suggested that low frequency (2-4Hz) stimulation resulted in the release of endorphin and high frequency ) the release of encephalin [55]. Low frequency stimulation produced analgesia of slower onset but longer duration of time. High frequency stimulation resulted in more rapid onset but shorter duration [55]. Current intensity was usually increased to a degree just less than what caused discomfort or at a degree tolerable to patients.
Tang W et al 2013 [56] evaluated the impacts of electroacupuncture at bilateral PC6 at different frequencies in patients undergoing laparoscopic surgery under general anaesthesia. Patients were randomised into 2Hz electro-acupuncture (group A), 2Hz/100Hz electro acupuncture (group B), 100Hz electro acupuncture (group C) and control (group D). The incidence and severity of PONV in group B was apparently lower than other groups (P<0.01).
Study by Lin JG et al 2002 [57] showed that the incidence of nausea during the first 24h after surgery was significantly reduced in low (2Hz) and high (100Hz) electro-acupuncture groups compared to control and sham electro-acupuncture. Both high-and low-frequency electrical stimulation also reduced postoperative analgesic requirement, with best results in high-frequency stimulation. Use of electro-acupuncture also resulted in a decrease in the incidence of opioid-related side effects after lower abdominal surgery.
Acupoint injections combine the effect of both acupoint stimulation and drugs, with Chinese and Western application, and had been proved to be effective in PONV prevention and treatment.
Cupping therapy acts on the meridians and acupoints along the pores and skin, mediate the flow of qi and blood, and balances yin and yang. It is effective in PONV prevention [38].
Catgut embedment involves the theory of acupuncture and needle retention. It forms a complex, soft and durable stimulation, reduces pain and remains longer duration than manual acupuncture. It was found to be significantly more effective than medication in reducing pain, nausea and vomiting [40].
Acupoints (unilateral/bilateral). A trial indicated neither unilateral nor bilateral application of acupressure significantly affected the incidence of nausea and vomiting [58] while another study showed both had mixed effects, although bilateral application seemed to have more consistent complete response (PONV incidence and antiemetic use) [59].
Needle size and depth of needle insertion. Shorter needles are usually used near the face and eyes, while longer needles are used in more fleshy areas. Thicker needles are often used on more robust patients.
Needles are usually inserted until "deqi" to achieve stimulation and to a degree which cause least pain and discomfort to patients.

Side effects
Overall, acupuncture is safe though there were few reports on local erythema with electro-acupuncture; and redness, erythema, swelling, tenderness and paraesthesia with acupressure bands. The effects were local and no major adverse events followed.

Use of rescue anti-emetics
The intervention group seemed to be effective in reducing the use of anti-emetics rescue therapy.

Quality evaluation GRADE, CONSORT AND STRICTA FOR TCM.
Most of the studies on PC6 combined with other acupoint(s) and other acupoint(s) did not emphasis the details of blinding and allocation concealment. Most of these studies were conducted in mainland China.
Although high quality evidence doesn't necessarily imply strong recommendations, and strong recommendations can arise from low quality evidence [13], studies in the future should follow the standard guideline for better quality of evidence.
Future studies should be carried out according to recommendations for better quality of evidence.

Updated from Previous Systematic Reviews[1],[60,61].
1 Efficacy of different type of acupuncture on PC6, PC6 combined with other acupoint(s), and other acupoint(s)) were compared. Studies were further divided according to time of PONV, according to availability of data. 2 Optimal timing, technique of intervention, side effects and use of rescue therapy were considered. 3 Heterogeneity was minimized, with studies varied significantly from others in combination of intervention, study settings or populations were excluded.
Other Considerations. For combination of interventions, the order of intervention might need to be considered, as it might affect the efficacy and study outcome. For example, Norheim AJ et al 2010 [62] and Liodden I et al 2011 [63] performed PC6 acupuncture followed by acupressure in children undergoing tonsillectomy and/or adenoidectomy. Results showed less vomiting in the treatment group compared to control in both studies. On the other hand, Shenkman Z et al 1999 [64] performed a study with PC6 acupressure followed by acupuncture, no significant differences in retching and vomiting were demonstrated between the treatment and control group. Hence, type and order of intervention might contribute to the difference in results.
Previous studies on combinations of interventions such as acupuncture with transdermal scopolamine vs. transdermal scopolamine [65], acupoint sticking therapy with massage vs. standard care [66], electro-acupuncture with tropisetron vs. tropisetron [67] at bilateral PC6 and ST36 demonstrated significant better results in intervention compared to control group.

Limitations
1 There were articles which were not included due to lack of studies to form subgroup under the same type of intervention for meta-analysis. Studies such as laser stimulation [68] and intraoperative stimulation with conventional nerve stimulator [69] also demonstrated the effectiveness of PC6 stimulation on reducing nausea and vomiting compared to control. The use of semi-permanent acupuncture needles at bilateral PC6 was shown to reduce the severity of nausea in the second 24 hours, and have greater effect on patients who had nausea and vomiting after a previous anaesthetic [70]. 2 Comparison between PC6 intervention with anti-emetics and efficacy of PC6 intervention at late PONV could not be evaluated due to lack of studies. 3 Studies in the PC6 combined with other acupoint(s) and other acupoint(s) could not be further subgrouped according to type of acupuncture and time of PONV due to lack of studies.

Conclusion
Acupuncture for prevention and treatment of PONV is worth popularising for its efficacy, safe, cost effectiveness and benefits. It also has analgesic effects and could serve as pain relief.
Besides PC6, PC6 combined with other acupoint(s) and other alternative acupoint(s) might be beneficial in prevention and treatment of PONV, the evidence justifies future highquality studies.

Supporting Information
Checklist S1. PRISMA Checklist. (DOCX) Table S1. Data summary and GRADE of the 16 studies included in meta-analysis for PC6 (A). Data summary and GRADE of the 6 studies included in meta-analysis for PC6 combined with other acupoint(s) (B). Data summary and GRADE of the 8 studies included in meta-analysis for other acupoint(s) (C). (DOCX)