Use of Acupuncture in the Control of Chemotherapy-Induced Nausea and Vomiting

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Original Article

Ting Bao, MD, Baltimore, Maryland

Key Words tiemetic agents have substantially improved the control Acupuncture, electroacupuncture, acupressure, electrostimula- of CINV. However, a study suggests that CINV remains tion, chemotherapy, nausea, vomiting, antiemetic a significant problem among these patients.2 In addition, pharmacologic antiemetic agents are expensive and as- Abstract sociated with potential side effects, and therefore explor- Chemotherapy-induced nausea and vomiting (CINV) is one of the ing nonpharmacologic options for controlling CINV is most common and feared side effects of chemotherapy. Despite recent advances in pharmacologic antiemetic therapy, additional important. Acupuncture is an ancient traditional Chi- treatment for breakthrough CINV is needed. Acupuncture is a safe nese medical technique proven to be effective and safe in medical procedure with minimal side effects; several randomized treating multiple conditions, including nausea and vom- controlled clinical trials have suggested its efficacy in controlling iting caused by pregnancy,3 sea sickness,4 surgery,5 and this side effect. A recent meta-analysis of those trials demonstrat- chemotherapy.6 This article summarizes the pathology of ed that acupuncture significantly reduced the proportion -of pa tients experiencing acute chemotherapy-induced vomiting. Those CINV and modern pharmacologic antiemetic therapy, trials, however, did not show that acupuncture significantly alle- and discusses the use of acupuncture to control CINV. viated acute chemotherapy-induced nausea or delayed CINV. The clinical relevance of these results were limited by the fact that they predated the use of aprepitant and that only 1 or 2 acupuncture CINV points were stimulated during acupuncture treatment. More clinical trials to study the effect of acupuncture with additional anti- Background emetic acupuncture points in adjunct to modern pharmacologic Before the advent of 5-hydroxytryptamine-3 (5-HT )– antiemetic therapy are needed. (JNCCN 2009;7:606–612) 3 receptor antagonists and neurokinin-1–receptor antagonists, CINV was poorly controlled. Among patients Chemotherapy-induced nausea and vomiting (CINV) is undergoing chemotherapy, 70% to 80% experienced one of the most common and feared treatment-related severe CINV.7 Risk factors for CINV include female side effects among patients with cancer. As a result, nu- gender, young age, and treatment with highly emeto- tritional status, quality of life, and treatment adherence genic chemotherapy.8 Chemotherapy agents are divided may be severely compromised.1 Over the past 20 years, into 4 emetogenic risk levels: high (> 90%), moderate better understanding of the physiology of CINV and (30%–90%), low (10%–30%), and minimal (< 10%).1,9 subsequent development of modern pharmacologic an- CINV can be either acute, delayed, or anticipatory. Acute CINV occurs within 24 hours of chemotherapy, usually beginning within 2 to 4 hours and peaking in the From Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, 8 Baltimore, Maryland. first 4 to 6 hours. Delayed CINV occurs from day 2 to 8 Submitted November 15, 2008; accepted for publication 6 of chemotherapy. Anticipatory CINV occurs before February 16, 2009. chemotherapy treatments in patients who have previ- The author has no financial interest, arrangement, or affiliation with the manufacturers of any products discussed in the article or ously experienced significant CINV.8 Most antiemetic their competitors. research focuses on reducing acute and delayed CINV, Correspondence: Ting Bao, MD, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, 1650 Orleans Street, CRB-186, with the understanding that this would result in better Baltimore, MD 21231. E-mail: [email protected] control of anticipatory CINV.

Acupuncture for Chemotherapy-Induced Nausea and Vomiting

Mechanism of Action Substance P has also been suggested to play an Animal studies suggest that emetogenic chemother- important role in CINV. Its receptors, neurokinin-1 apy agents entering the body through either mucosa receptors, are located throughout central and periph- or blood stimulate enteroendocrine cells located in eral nervous systems, including the area postrema and the gastrointestinal mucosa of the proximal small gastrointestinal tract. Aprepitant is the first drug in intestine.8 Consequently, the enteroendocrine cells the class of neurokinin-1–receptor antagonists. Two release local mediators, such as 5-HT, substance P, phase III, randomized, controlled trials showed that and cholecystokinin.8 These mediators then bind to the 3-drug combination of aprepitant, ondansetron, the corresponding receptors at the end of the vagal and dexamethasone controlled CINV significantly afferent fibers located nearby, triggering the afferent better than the 2-drug combination of ondansetron stimuli and reaching the loosely organized neuro- and dexamethasone during a 5-day study in patients nal areas within the medulla.10 Those neurons then undergoing highly emetogenic chemotherapy.17,18 coordinate the emetic reflex and result in nausea These results led the FDA to approve adding aprepi- and vomiting.8 tant to antiemetic regimens for patients undergoing Other studies suggest that CINV occurs after highly emetogenic chemotherapy. neurotransmitters, such as dopamine, 5-HT, or hor- monal stimuli, bind to area postrema, a structure located in the caudal end of the fourth ventricle,11 or Management the limbic forebrain.12 Based on available evidence, current antiemetic guidelines recommend a 3-drug combination of a

5-HT3–receptor antagonist, dexamethasone, and Pharmacologic Antiemetic Therapy aprepitant for patients undergoing highly emetogenic Corticosteroid has been used extensively as an an- chemotherapy. For moderately emetogenic chemo- tiemetic agent over the past 25 years, although its therapy, a 2-drug combination with a 5-HT3–recep- antiemetic mechanism is not well understood.8 Do- tor antagonist and dexamethasone is recommended. pamine, 5-HT, and substance P are believed to be For low emetogenic chemotherapy, dexamethasone the important neurotransmitters mediating CINV.8 with or without dopaminergic antagonists is recom- As a result, antiemetic medications are divided into mended. No antiemetic agent is recommended for 8 3 main categories: dopaminergic, 5-HT3–receptor, chemotherapy agents with minimal emetic risk. and neurokinin-1–receptor antagonists. Although Using the current regimens, CINV is much less dopaminergic antagonists, such as prochlorperazine, prevalent or severe. However, several questions re- haloperidol, and metoclopramide, are the oldest and main. Although chemotherapy-induced vomiting most widely used antiemetic drugs, they are associ- has been much better controlled by the newly devel- ated with lower therapeutic index and greater poten- oped pharmacologic agents, chemotherapy-induced tial side effects. nausea is not.2 This problem was illustrated in a phase Understanding the important role 5-HT played in III, randomized, controlled trial assessing the role of preventing CINV has revolutionized therapy;8 it has aprepitant in patients receiving anthracycline and been regarded as the most important receptor in acute cyclophosphamide, in which aprepitant significant- 13,14 CINV. 5-HT3 receptors are located in both central ly lowered the proportion of patients experiencing (area postrema) and peripheral nervous systems (va- chemotherapy-induced vomiting (76%–59%) but 15 gal afferents). Selective 5-HT3–receptor antagonists did not change the rate at which they experienced have been established as standard CINV prophylactic nausea.19 Lastly, even with the 3-drug regimen, 11% therapy for patients undergoing moderately or highly to 17% still experience acute CINV.17,18 Additional emetogenic chemotherapy. Common side effects as- therapy is needed for breakthrough CINV and to sociated with 5-HT3–receptor antagonists are mild better control nausea. Nonpharmacologic therapy, headache, transient liver enzyme elevation, and con- such as acupuncture, has therefore attracted signifi- 8 stipation. Although 5-HT3–receptor antagonists are cant research interest because of its minimal side ef- highly effective in preventing acute CINV, they have fects and reported efficacies in relieving nausea and notably lower efficacy in preventing delayed CINV.16 vomiting caused by multiple conditions.

Bao

Acupuncture Acupuncture points can be stimulated in vari- Acupuncture is a traditional Chinese medicine ous ways. With manual acupuncture, the filiform technique that involves inserting and manipulat- acupuncture needle is inserted in an acupuncture ing filiform needles in predefined points on the skin point and manually rotated to stimulate the point. (i.e., acupuncture points) to achieve therapeutic effect. With electroacupuncture, acupuncture points are It has been widely used in China to treat multiple med- stimulated by passing electrical current through in- ical conditions, such as pain, nausea, and vomiting. serted needles. Electrical current may also be passed Acupuncture was introduced in the United States in through an electrode on the skin without inserting 1971 after the New York Times reporter James Reaton acupuncture needles, a technique called noninvasive reported that acupuncture relieved his postoperative electrostimulation. Acupressure is a form of modified pain after an emergency appendectomy while in Bei- acupuncture that replaces needles with physical jing.20 The use of acupuncture in controlling CINV pressure generated with either a finger or a device was then acknowledged by the National Institutes of such as an embedded stud in an elastic wrist band. Health 1997 Consensus Statement, which claimed that promising research suggested that acupuncture was efficacious in reducing CINV.21 However, at that Acupuncture Research time, only 2 small clinical trials on acupuncture for In 2005, Ezzo et al.22 published a comprehensive me- controlling CINV had been published.22 ta-analysis of 11 randomized clinical trials (N = 1247) Although studies have not been able to fully evaluating the effect of acupuncture point stimula- explain the mechanism of acupuncture, experts tion in controlling CINV. Those trials were pub- have proposed that it works through its effect on lished between 1987 and 2003, and the sample sizes neurotransmitters and neurohormones.23,24 Animal ranged from 1031 to 747 patients.32 Among the 10 research suggests that acupuncture accomplishes its trials that reported chemotherapy regimen, all pa- anesthetic effect by stimulating nerves in the mus- tients underwent moderately to highly emetogenic cle, which then relay the signal to the spinal cord, chemotherapy; 8 trials used a antiemetic regimen

midbrain, and hypothalamus-pituitary system, which containing the 5-HT3–receptor antagonist ondanse- in turn lead to the release of neurotransmitters and tron, and the other 3 trials used methotrexate alone, hormones (i.e., endorphins and enkephalins).25,26 methotrexate with prednisone, or methotrexate with Acupuncture may work in a similar manner to re- dopaminergic antagonists.22 In addition, all of the lieve nausea and vomiting, although limited data are antiemetic regimens predated aprepitant. available to confirm this theory. In addition, modern Four acupuncture point–stimulating modalities human neuroimaging studies suggest that stimulat- were used to control CINV: manual acupuncture, ing acupuncture points resulted in responses to the electroacupuncture, noninvasive acupuncture point cortical and subcortical areas in the brain.27 stimulation, and acupressure.22 One trial with 80 Deciding which acupuncture points to stimulate patients examined the effect of manual acupunc- is the most important part of acupuncture treatment. ture at P6.33 Three trials (N = 134) examined the More than 300 acupuncture points are located on effect of electroacupuncture on P6 (2 trials)31,34 and the body and each point has its own therapeutic in- on P6 plus ST36 (1 trial).35 Four trials (N = 149) dex. Picking the corresponding acupuncture points studied the effect of noninvasive electrostimulation for specific medical conditions is critical. Multiple on P6.6,36–38 One trial (N = 747) studied both elec- acupuncture points, such as pericardium 6 (P6), trostimulation and acupressure on P6.32 Two trials stomach 36 (ST36), stomach 44 (ST44), and con- (N = 137) studied acupressure on P6 alone39 and P6 vention vessel 12 (CV12), have been used to reduce plus ST36.40 Minimal side effects were reported, in- nausea and vomiting in China.28 Acupuncture re- cluding skin discomfort and irritation, transient skin search on reducing nausea and vomiting, however, rash, and electrical shock, and peripheral neuropa- has primarily studied stimulating one acupuncture thy in 1 patient in an electroacupuncture trial.22 point: P6 (Neiguan in Chinese).29,30 P6 locates 3 fin- The data were first analyzed by combining all gers below the flexor crest and between the tendons acupuncture point stimulation modalities. Nine tri- of the flexor carpi radialis and palmaris longus.22 als evaluated the effect of acupuncture point stimu-

Acupuncture for Chemotherapy-Induced Nausea and Vomiting lation on acute vomiting and showed that the pro- was further confirmed by a subsequent mini systemic portion of episodes was significantly lower in the review (N = 482) comparing acupressure and usual acupuncture point stimulation group than the con- care with usual care alone.43 trol (22%, 155 of 744 patients vs. 31%, 154 of 500 The meta-analysis by Ezzo et al.22 is the most patients; P = .04).6,22,31–35,37–39 The mean number of comprehensive summary of clinical research on the acute vomiting episodes, however, did not differ be- role of acupuncture point stimulation in control- tween the groups.6,22,31–35,37–39 ling CINV. Its conclusion that acupuncture point Those results were also reflected in both sham- stimulation decreases the proportion of patients ex- and non–sham-acupuncture controlled trials.22 periencing acute chemotherapy-induced vomiting Among 7 trials assessing the effect of acupuncture concurred with the previous systemic review and point stimulation on acute nausea severity, no sig- meta-analysis.44,45 It suggested that acupressure may nificant difference was seen between the groups P( relieve chemotherapy-induced nausea, even though = .10).6,22,32,33,36–38,40 In 3 noninvasive acupuncture the studies were limited by lack of effective control point stimulation trials, it had no benefit on delayed arm to tease out placebo effect. It also suggested vomiting episodes (P = .80).6,22,41,42 Results of 5 tri- differences among acupuncture point stimulation als evaluating the effect of noninvasive acupuncture modalities, showing invasive point stimulation was point stimulation on delayed nausea also showed no more effective than noninvasive point stimulation benefit P( = .80).6,22,32,37,38,40 in reducing acute CINV.22 The meta-analysis by Ezzo The data were then analyzed according to et al.22 is cited multiple times by review articles and treatment modalities. The 4 acupuncture trials oncology practice guidelines.30,46,47 (N = 214)31,33,35 showed that manual acupuncture The clinical relevance of this meta-analysis and electroacupuncture significantly decreased the remains unclear because of several limitations, proportion of patients experiencing acute chemo- some noted by the authors themselves.22 First, the therapy-induced vomiting, from 60% (71 of 119) in most robust data of this meta-analysis came from the control group to 37% (35 of 95) in the acupunc- 3 electroacupuncture trials, with a combined total ture group (P = .01).22 Among these, however, the of only 139 patients. Such a small sample size in- trial that used only manual acupuncture showed no creased the risk for sampling bias and lessened the difference between the groups.33 The 3 remaining tri- representativeness of the data. In addition, none of als using electroacupuncture (N = 139)31,34,35 showed the 3 electroacupuncture trials used an antiemetic that a lower proportion of patients who underwent regimen containing a 5-HT3–receptor antagonist, electroacupuncture experienced acute chemothera- which is part of the standard antiemetic regimen for py-induced vomiting compared with controls; how- highly emetogenic chemotherapy and subsequently ever, none of the electroacupuncture trials used an caused the data to be less interpretable in current antiemetic regimen containing a 5-HT3–receptor clinical practice. antagonist.22 Manual acupuncture did not signifi- Furthermore, all 11 trials predated aprepitant, cantly decrease acute chemotherapy-induced nausea making the data less clinically relevant. In addition, either.33 None of the acupuncture trials effectively among the 11 trials analyzed, 9 trials stimulated P6 studied the effect of acupuncture on delayed CINV.22 point alone and 2 stimulated P6 and ST36 points. The 4 noninvasive electrostimulation trials In traditional Chinese medicine practice, multiple (N = 629)6,32,37,38 showed that electrostimulation did antiemetic acupuncture points, including P6, ST36, not alleviate either acute or delayed CINV.22 Al- ST44, and CV12, are stimulated simultaneously. though the 3 trials using acupressure (N = 620)32,39,40 Without examining the effect of the most effective showed that this technique did not significantly acupuncture point combination, claiming that acu- decrease acute chemotherapy-induced vomiting puncture did not work in certain conditions is diffi- (P = .3),22 they did show that it significantly -de cult. Finally, none of the studies explored the mecha- creased the severity of acute chemotherapy-induced nism of acupuncture in reducing CINV. nausea (P = .03), although none of the trials had a A PubMed search of key words—“acupuncture,” sham-acupressure control group.22 The effect of acu- and “chemotherapy-induced nausea and vomiting”— pressure in reducing chemotherapy-induced nausea produced a few clinical trials that were not included

Bao

in the analysis by Ezzo et al.22 These trials investigat- men. It showed a significantly lower need for rescue ed the additive benefit of acupuncture to 5-HT3–re- antiemetic medication (P = .001) and fewer episodes ceptor antagonist antiemetic regimen. None of those of acute chemotherapy-induced vomiting (P = .01) trials, however, used the standard 3-drug antiemetic in the acupuncture treatment group than the no chemotherapy regimen. acupuncture control group.51 This trial is unique be- Published in 2003, a Swedish clinical trial evalu- cause it allowed experienced acupuncturists to de- ated the role of acupuncture combined with on- cide which acupuncture points to use and thus pro- dansetron in reducing cyclophosphamide-induced vided individualized acupuncture treatment to the nausea and vomiting in patients with rheumatic dis- patients; the most commonly used points were PC6, eases.48 It was a small study with 39 patients treated ST36, CV12, and LI4. However, it is limited by its with acupuncture P6 or in the ear unilaterally or small sample size, crossover design that could intro- bilaterally. Using the patients as their own con- duce carry-over effect, and lack of sham acupuncture trols, the investigators showed that the combined control arm. acupuncture/ondansetron treatment was superior Although all of these trials investigated the addi- to ondansetron treatment alone in reducing CINV tional benefit of acupuncture/acupressure to 5-HT3– (nausea: P < .0001; vomiting: P < .0035).48 This receptor antagonist, all of them predated aprepitant, study, however, was limited by its small sample size, and none used a concurrent 3-drug antiemetic regi- complicated, difficult-to-follow study design, and, men. It is encouraging to note that the more mod- especially, the lack of effective blinding device and ern acupuncture studies have begun to use more control group. acupuncture points to control CINV. Those studies, In 2005, Roscoe et al.49 published a 3-arm clini- however, did not have effective sham-acupuncture cal trial examining the effect of acustimulation wrist control arms to tease out placebo effect. In addition, bands in reducing CINV in patients with breast none of the studies explored the mechanism of acu- cancer. It was a large sample-size, well-designed puncture in controlling CINV. study with 96 patients experiencing chemotherapy- induced nausea randomized into active acustimulation, sham acustimulation, or no stimulation arm. Conclusions No difference was seen among the 3 arms in acute Current acupuncture research on CINV is limited nausea, delayed nausea, vomiting, quality of life, by small sample size and outdated concurrent anti- or antiemetic medication use. The selection of the emetic pharmacologic therapy. However, studies sug- sham point for acustimulation, which is an active gest a role of acupuncture in controlling CINV even acupuncture point by itself—Triple Heater 5 point— though its implication in the current clinical prac- may be used to explain the lack of difference between tice remains unclear. Further acupuncture research the real versus sham acustimulation. However, the should consider using additional antiemetic acu- lack of difference between the no-stimulation and puncture points, with bigger sample sizes, an effec- the other 2 arms is difficult to explain. The question tive sham acupuncture control arm, and as adjunct of the efficacy of self-administrated acustimulation to the standard 3-drug antiemetic regimen. Further in controlling CINV is subsequently raised. acupuncture research should also explore the mecha- In 2007, an acupressure study of 100 oncology nism of acupuncture. patients undergoing chemotherapy and experiencing breakthrough CINV despite antidopaminergics and antiemetic regimens containing a 5-HT3–receptor References antagonist showed that 68% patients experienced 1. Naeim A, Dy SM, Lorenz KA, et al. Evidence-based 50 recommendations for cancer nausea and vomiting. J Clin Oncol relief with P6 acupressure treatment. 2008;26:3903–3910. 51 In 2008, Guttschling et al. published the final 2. Hickok JT, Roscoe JA, Morrow GR, et al. Nausea and emesis result of a randomized multicenter crossover study of remain significant problems of chemotherapy despite prophylaxis 23 pediatric oncology patients treated with highly with 5-hydroxytryptamine-3 antiemetics: a University of Rochester James P. Wilmot Cancer Center Community Clinical Oncology emetogenic chemotherapy and undergoing a con- Program Study of 360 cancer patients treated in the community. Cancer 2003;97:2880–2886. current 5-HT3–receptor antagonist antiemetic regi-

Acupuncture for Chemotherapy-Induced Nausea and Vomiting

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