Effect of transcutaneous electrical acupoint stimulation combined with palonosetron on chemotherapy-induced nausea and vomiting: a single-blind, randomized, controlled trial

Transcatheter arterial chemoembolization (TACE) is a palliative treatment of advanced primary and metastatic liver cancer. However, chemotherapy-induced nausea and vomiting (CINV) adversely affects the quality of life (QoL) of patients who undergo this intervention. It is estimated that 70%–80% of cancer patients who received chemotherapy developed CINV, and nausea and vomiting is one of the most debilitating symptoms induced by chemotherapy [1, 2]. Severe vomiting can cause dehydration, electrolyte disturbances, muscle weakness, and weight loss; it may even be life-threatening by inducing acute hemorrhage of the upper digestive tract. CINV drastically lowers QoL and treatment compliance, and it may also affect the success of a specific treatment protocol [3].

Despite improvements in the prevention and treatment of CINV, including the use of type 3 serotonin (5-HT₃) receptor antagonists [4, 5], there are still potential risks of adverse effects [1, 2]. Therefore, the need for further relief has led to an interest in non-pharmacological therapies [6, 7]. Previous studies have demonstrated the efficacy of acupuncture, which has been used for more than 2500 years in traditional Chinese medicine to cure disease and relieve accompanying symptoms [8–10]. In 1979, acupuncture was approved by the World Health Organization for the treatment of nausea and vomiting resulted from disordered function of the stomach [11]. Some randomized clinical trials have found that acupuncture is an effective palliative treatment of cancer patients, especially for reducing chemotherapy-induced adverse effects such as nausea and vomiting [12]. Transcutaneous electrical acupoint stimulation (TEAS) is an electrical stimulation technique that sends electrical impulses into acupoints through electrodes on the skin surface. TEAS is noninvasive, is easy to use, and does not have obvious adverse effects.

Although noninvasive electro-acupuncture has been shown to benefit patients suffering from CINV [13–15], studies on TEAS combined with anti-emetics, particularly in patients with refractory symptoms or receiving highly emetogenic chemotherapy drugs, are needed to determine if this regimen is also safe and effective to relieve patients’ gastrointestinal discomfort after chemotherapy [16]. In our previous study, we found that electro-stimulation on the acupoint Yongquan (K1) combined with anti-emetics did not result in initial prevention of cisplatin- or oxaliplatin-induced nausea or vomiting [17]. However, it is possible that an extended treatment time and the selection of different acupoints (particularly in the form of combined points) might offer more promising results. Previous studies indicated that stimulation on the acupoint Neiguan (P6) was an effective anti-emetic technique for the prevention of CINV [18, 19], and stimulation on the acupoints Zusanli (ST36) and Hegu (LI4) showed similar results [20–23]. Stimulation on two or more acupoints may improve anti-emetic efficacy, but it lacks the support of clinical trial data. In this study, we chose to stimulate the three acupoints P6, ST36, and LI4 together as a new regimen, which also considered traditional Chinese medicine’s “meridian” theory.

In this study, all participants were diagnosed with primary or metastatic liver cancer, and TACE with cisplatin was considered the optimal treatment. Because cisplatin is highly emetogenic, we used electrical stimulation (active acupuncture vs. placebo acupuncture) combined with a 5-HT₃ receptor antagonist, palonosetron. Participants were randomly assigned to the active-acupuncture or the placebo-acupuncture group. The acupoints LI4, P6, and ST36 were stimulated twice daily for 6 days. The effects of TEAS on nausea and vomiting, appetite, and QoL were also assessed.

Based on the finding that acupuncture was efficacious for the treatment of CINV, we proposed that electrical stimulation would be effective for patients receiving TACE. Thus, we designed the present single-blind, randomized, controlled trial to examine the safety and efficacy of active acupuncture compared with placebo acupuncture for the treatment of CINV.

We found no significant effect of TEAS in reducing CINV or improving QoL. However, electrical stimulation on acupoints LI4, P6, and ST36 did markedly relieve appetite loss from the second day after TACE.

CINV is typically associated with a high level of 5-HT, which activates 5-HT₃ receptors to stimulate vomiting centers. The introduction of 5-HT₃ receptor antagonists led to significant improvements in the control of acute nausea and vomiting, and 5-HT₃ receptor antagonists are now part of the standard regimen. However, a substantial proportion of patients continue to experience both acute and delayed CINV after moderately or highly emetogenic chemotherapy. Additionally, adverse events such as headache, constipation, abdominal pain, and dizziness may cause discomfort to patients [4, 30]. Palonosetron is a highly potent, second-generation, selective 5-HT receptor antagonist. One study showed that palonosetron hydrochloride reduced the occurrence rate of acute nausea and vomiting after highly emetogenic chemotherapy by 59.2% [4]. However, even if such a prophylactic approach is taken, sudden nausea and vomiting may still occur. Furthermore, the effectiveness of palonosetron hydrochloride for delayed vomiting remains unsatisfactory, with a reported occurrence rate of 45.3% at a dosage of 0.25 mg and 48.0% at a dosage of 0.75 mg [4]. Repeated administration did not improve results but did increase potential adverse effects and medical expenses. Therefore, to achieve better anti-emetic effects, palonosetron should be combined with other treatment approaches.

Electro-acupuncture was found to be effective in treating moderate CINV [31], with needles inserted into acupoints on the body, which were then attached to a device that generates continuous electric pulses using small clips. Electro-acupuncture might result in complications such as needle syncope, pain, and organ puncture. Furthermore, traditional electro-acupuncture using needles is not always convenient or available in all centers. TEAS is a novel and noninvasive method of acupuncture that has a similar mechanism of action to electro-acupuncture and is considered a safe and effective treatment.

In our study, all patients were successfully blinded and completed the entire study. The credibility rating in the two groups did not differ significantly. Acute CINV usually occurs within the first 24 h after drug administration, and most emetic chemotherapy drugs can trigger nausea and vomiting within 1 or 2 h after drug administration. In contrast, delayed CINV occurs 24 h after drug administration and may last for 6–7 days. Our present study suggested that electrical stimulation on acupoints, combined with 5-HT₃ receptor antagonists, could slightly reduce the occurrence rate of nausea and vomiting on day 0 and subsequent days (except on day 3), but the therapeutic efficacy was not significant compared with that of the placebo treatment (P > 0.05). Similarly, no significant differences were observed between the two groups with regard to the degree of nausea or vomiting on days 0–5. This indicates that electro-stimulation of the combined acupoints was not efficacious in augmenting the anti-emetic effects of 5-HT₃ receptor antagonists in preventing acute or delayed CINV.

One possible reason why the treatment of more acupoints did not increase the anti-emetic effects more than a regimen that treated only a single acupoint may be that most of the studies reported of these single-acupoint regimens were based on electro-acupuncture with the insertion of needles into the skin, rather than TEAS, which was used in our study. According to a meta-analysis by Ezzo et al. [16], acupressure or surface electro-stimulation may have weaker effects than electro-acupuncture with needles. However, to our knowledge, the electro-stimulation mechanism of multiple acupoints remains unclear, and related fundamental research is needed.

Although our study did not reach its primary endpoint, TEAS was shown to be effective in recovering patient appetites after chemotherapy, as indicated by the significant decrease of the anorexia VAS. The effect was observed as early as the first day after TACE, and the decrease of VAS was greater in the active-acupuncture group than in the placebo-acupuncture group. These results were in agreement with previous studies that demonstrated the therapeutic effects of acupuncture in patients with chemotherapy- or radiotherapy-induced anorexia [32–34]. Acupuncture may stimulate the stomach’s peristalsis and rapidly empty its contents, thus strengthening gastrointestinal motility and resulting in a sense of hunger [35]. This is the most effective way to rapidly improve the appetite; some patients even have a sense of hunger just 1 min after acupuncture. During the early stage of nausea, loss of appetite and feelings of discomfort are the major clinical manifestations. Based on our findings and those of previous reports, we think that a rapid improvement of appetite brought about by TEAS indicates an early sign of recovered gastrointestinal function. Furthermore, a rapid improvement of appetite can help improve patients’ entire recovery process, by reducing sodium electrolyte and energy metabolism disorders, by resulting in weight gain through an increase in food intake, and by improving the emotional state of patients and family members.

The frequency of adverse events in both groups was similar, and only two TEAS-treated patients complained of discomfort at the electrode patch site, which might be related to the acupuncture treatment. Therefore, the treatment was well tolerated and safe.

In summary, our study used combined acupoints P6, LI4, and ST36 rather than a single acupoint to treat CNIV. Although the occurrence rates of nausea and vomiting did not significantly decrease for patients with primary liver cancer who were treated with TACE, the anorexia VAS was significantly lower in the active-acupuncture group than in the placebo-acupuncture group, starting from the second day after TACE. The acupuncture treatment is low in cost, has few adverse reactions, and is simple to administer. Acupuncture may be an optional adjunctive treatment for palliative care; further studies using TEAS are warranted.