606 Original Article Use of Acupuncture in the Control of Chemotherapy-Induced Nausea and Vomiting 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 clini- cal 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 an- tagonists, 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. © Journal of the National Comprehensive Cancer Network | Volume 7 Number 5 | May 2009 Original Article 607 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 lo- cated 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. © Journal of the National Comprehensive Cancer Network | Volume 7 Number 5 | May 2009 608 Original Article 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