Chapter 40. Nausea and Vomiting

Nausea and vomiting are two of the most common side effects experienced by patients receiving chemotherapy.1 If not appropriately controlled, nausea and vomiting can lead to serious complications such as electrolyte imbalances and esophageal tears.2 It is much easier to prevent nausea and vomiting than to try to treat it once it has started. Although significant progress has been made in drug therapy for nausea and vomiting, these side effects continue to be some of the most worrisome and undesirable effects reported by patients receiving chemotherapy.

The etiology of nausea and vomiting is quite complex. The chemoreceptor trigger zone (CTZ), located outside of the blood-brain barrier, is activated by chemotherapy and other irritants. The CTZ is triggered by various neurotransmitters including dopamine, serotonin, histamine, and neurokinin-1 (substance P)3,4 (Figure 40-1). The activation of the CTZ stimulates the vomiting center. This process is common in chemotherapy-induced nausea and vomiting (CINV). In addition to the CTZ, the gastrointestinal tract (GI) tract releases serotonin in response to chemotherapy, which can also cause CINV.5 Our current antiemetic medications block these neurotransmitters to stop the initiation of CINV.

There are several risk factors that increase the possibility of experiencing CINV. The emetogenic potential of the chemotherapy agent or agents is probably the most important factor.5 Agents are classified into high, moderate, low, or minimal risk for causing CINV. These risk categories were developed based on the percentage of patients experiencing CINV when receiving a particular chemotherapy agent without an antiemetic medication5-11 (Table 40-1). Dose and rate of infusion of the agent can also affect risk. Generally, the higher the dose of chemotherapy, the higher the risk of CINV. Bolus infusions also tend to have higher risk of CINV than extended infusions. Younger patients (< 50 years old), women, patients with a history of motion sickness or nausea with pregnancy and patients with a history of poorly controlled CINV are at increased risk of developing problems despite adequate antiemetic treatment. Interestingly, a history of alcoholism can decrease a patient's risk of CINV.5,8,9,12,13 One theory is that this occurs because the patient's body has become desensitized to toxins and irritants.14

There are several types of CINV: acute, delayed, anticipatory, breakthrough, and refractory.4,5,11 Acute CINV is defined as nausea and vomiting that occurs within the first 24 hours following the administration of chemotherapy, but most commonly occurs within 5 to 6 hours of the dose. Delayed CINV develops more than 24 hours after chemotherapy is administered and can persist up to 7 days.11 Chemotherapeutic agents that commonly cause delayed CINV include cisplatin, carboplatin, cyclophosphamide, and doxorubicin11 (Table 40-2). Anticipatory CINV occurs after a negative experience with chemotherapy, and thus can only occur if chemotherapy has been previously received. The incidence of this type of nausea or vomiting ranges from 18% to 57%.11 Breakthrough CINV occurs when preventative antiemetic therapy fails and patients have at least one episode of nausea and/or vomiting that may require antiemetic treatment despite preventative antiemetic premedication. The last type is refractory CINV. This occurs when premedications and breakthrough therapy fail to prevent CINV from occurring after chemotherapy administration.

Antiemetics

Serotonin (5-Ht3) Receptor Antagonists

Serotonin is one of the most common neurotransmitters involved in CINV. The serotonin (5-HT3) receptor antagonists block serotonin in the GI tract and the CTZ to prevent CINV.14 There are four 5-HT3 receptor antagonists on the market in the United States4,8,9,14,15 (Table 40-3). These agents are effective in the prevention of acute CINV and have a limited role in delayed CINV (with the exception of palonosetron). Palonosetron has a longer half-life and is the only one in the class FDA-approved for both acute and delayed CINV in moderately emetogenic chemotherapy. There is currently no data to support superiority of one agent over another in the prevention of acute CINV.14 Choice of agent should be based on availability and cost. The oral route has been shown to be just as effective as the IV route and, therefore, the oral route is preferred for prevention of CINV because of ease of administration and decreased cost.11,14 Another option available is topical granisetron. This is applied 24 to 48 hours prior to chemotherapy and can remain on the skin for up to 7 days. The most common toxicities are headache and constipation.14,15 An infrequent, but more serious, toxicity is the ability of the 5-HT3 receptor antagonists to cause QT prolongation, although this has not been shown to be clinically significant to date.14

Corticosteroids

Corticosteroids can be used alone for the prevention of CINV with low-risk chemotherapy agents. Dexamethasone is the most commonly used corticosteroid, although one corticosteroid has not been proven superior to another4,14 (see Table 40-3). Corticosteroids are commonly used in conjunction with a 5-HT3 receptor antagonist with or without aprepitant for the prevention of CINV with moderate or high emetogenic chemotherapy agents or regimens to improve the efficacy of these agents.7,8,14,16 The mechanism of action is not well understood, but one theory is that they prevent serotonin release in the GI tract and block the 5-HT3 receptors in the GI tract as well.7 Oral and IV routes are considered equivalent.14 Since the use of corticosteroids for CINV is only short-term, the most common toxicities are generally limited to GI upset, insomnia, fluid retention, increased appetite, and increased blood sugars.14,15

Neurokinin-1 Receptor Antagonists

The neurokinin-1 (NK-1) receptor antagonists are a new class of antiemetics. Aprepitant and the IV prodrug, fosaprepitant dimeglumine, are the only two agents from this class currently approved in the United States. They are approved for prevention of acute and delayed CINV with highly emetogenic agents and with the cyclophosphamide/doxorubicin combination (see Table 40-3). The NCCN guidelines also recommend use with certain moderate emetic risk agents that have the potential for delayed CINV11 (see Table 40-2). Substance P exerts its effect on the NK-1 receptors causing nausea and vomiting. Aprepitant and fosaprepitant dimeglumine block substance P, thus preventing nausea and vomiting.4,14 The oral route is preferred unless the patient is having difficulty taking oral medications; the IV route is approved on day 1 only before chemotherapy. The most common side effects are headache, abdominal pain, and mild transaminase elevations.14,15 In addition, aprepitant is metabolized by CYP 3A4, and is a substrate and moderate inhibitor of CYP 3A4 so drug interactions should be considered. Important drug interactions include oral contraceptives, warfarin, and dexamethasone.17,18 This is why the dexamethasone dose should be decreased by 50% when given with aprepitant.

Dopamine Receptor Antagonists

Dopamine is a common neurotransmitter affecting the CTZ resulting in CINV4,5 (see Figure 40-1). Common dopamine receptor antagonists are the phenothiazines (prochlorperazine, promethazine), the butyrophenones (droperidol, haloperidol), and metoclopramide (Table 40-4). These agents are used for breakthrough nausea and vomiting. Toxicities include sedation and extrapyramidal side effects.4,5,15 A black box warning has been added to the package insert for metoclopramide warning of tardivedyskinesia with high doses or long-term use of metoclopramide. These dyskinesias may continue after the metoclopramide is discontinued.19

Cannabinoids

Cannabinoids produce their antiemetic activities through various effects on the CNS and GI tract, including activity at the cannabinoid receptor5,14 (see Table 40-4). The cannabinoid dronabinol is a Schedule III controlled substance that is particularly helpful for patients with refractory nausea and vomiting. Side effects include sedation, dysphoria, dizziness and dry mouth, and elderly patients may be more sensitive to these side effects.5,8,15 These agents may also increase appetite, which may be beneficial in patients with refractory nausea and vomiting resulting in weight loss.

Prevention of Acute Chemotherapy-Induced Nausea and Vomiting

Guidelines exist from several organizations on the treatment and prevention of CINV. The most commonly used guidelines are the National Comprehensive Cancer Network (NCCN) guidelines, which are updated at least annually, the American Society of Clinical Oncology (ASCO) guidelines updated in 2006 and the Multinational Association of Supportive Care in Cancer (MASCC) guidelines updated in 2008.10,11,17

For highly emetogenic chemotherapy or for the combination of cyclophosphamide/doxorubicin, the recommendation is to give a 5-HT3 receptor antagonist, dexamethasone and aprepitant prior to the chemotherapy10,11,17 (see Table 40-3). An agent for breakthrough nausea and vomiting should be prescribed for use on an as needed basis1,4,5,10,11,14,15,17 (see Table 40-4).

For moderately emetogenic chemotherapy, a 5-HT3 receptor antagonist with dexamethasone should be used10,11,17 (see Table 40-3). The NCCN guidelines recommend adding aprepitant for regimens containing drugs known to cause delayed CINV such as carboplatin and ifosfamide. An agent for breakthrough nausea and vomiting should be prescribed for use on an as needed basis1,4,5,10,11,14,15,17 (see Table 40-4).

For low emetogenic risk agents, the recommendation is a single-agent antiemetic such as dexamethasone given 30 to 60 minutes prior to chemotherapy administration.10,11,17 An agent for breakthrough nausea and vomiting should be prescribed for use on an as needed basis. For minimal risk agents, scheduled antiemetics should be avoided, and antiemetics should only be used on an as needed basis.1,4,5,10,11,14,15,17 (see Table 40-4).

Treatment of Acute Chemotherapy-Induced Nausea and Vomiting

Even with adequate prevention for CINV, patients may experience breakthrough CINV within the first 24 hours after chemotherapy. There are many drugs available for treatment of breakthrough CINV with a variety of factors to consider when choosing an agent1,4,5,10,11,14,15,17 (see Table 40-4). When choosing an agent, it is important to remember to use an agent with a different mechanism of action than was prescribed for prevention of acute CINV. In order to get the CINV controlled, it may be helpful to schedule the breakthrough antiemetic around the clock until the CINV subsides.

Prevention of Delayed Chemotherapy-Induced Nausea and Vomiting

For highly emetogenic agents and moderately emetogenic agents with a high risk of delayed CINV as identified by the NCCN guidelines, if aprepitant was given on day 1 of chemotherapy, then it should be continued on days 2 and 3 at 80 mg orally daily. Dexamethasone 8 mg orally daily should also be continued for two to three more days after chemotherapy to prevent delayed CINV.5,11

For moderately emetogenic agents when aprepitant is not used, dexamethasone 8 mg orally twice daily should be used for 2 to 4 days following chemotherapy.5 As previously stated, palonosetron is FDA-approved for prevention of both acute and delayed nausea and vomiting for moderately emetogenic agents and may provide added protection against delayed nausea and vomiting when used as a component of the acute prophylaxis regimen.

Treatment of Delayed Chemotherapy-Induced Nausea and Vomiting

Treatment would include the same breakthrough medications used in the treatment of acute CINV, keeping in mind that it is much harder to treat delayed CINV than acute CINV1,4,5,10,11,14,15,17 (see Table 40-4).

Anticipatory Nausea and Vomiting

Anticipatory nausea is more common than anticipatory vomiting, but both are conditioned responses, so they occur only after a poor experience with chemotherapy.11 Benzodiazepines can help control this type of nausea and vomiting. Lorazepam is the most commonly used benzodiazepine for this purpose, and is usually given in combination with other antiemetics for CINV5,8,11 (see Table 40-4). The most common toxicities are sedation, dizziness, and amnesia.5

Postoperative nausea and vomiting (PONV) are two of the most common problems following surgery and anesthesia and can result in unanticipated hospital admissions.20-22 The Society for Ambulatory Anesthesia published guidelines for the management of PONV in 2007. Patients at increased risk of PONV include female sex, nonsmokers, history of PONV or motion sickness, and postoperative opioid use.20,21,23 The addition of each risk factor increases the risk of PONV by 20%. The type of anesthetic used, the duration of surgery, and the type of surgery also play a role in the risk of PONV.20,21

Prevention of Postoperative Nausea and Vomiting

Strategies such as avoiding certain anesthetics, minimizing intraoperative and postoperative opioids, and use of regional anesthetics are used to decrease the risk of PONV.20,21 Patients with low risk of PONV will probably not benefit from prophylaxis and should not receive this treatment unless they are at risk of medical adverse effects from vomiting including patients with wired jaws and increased intracranial pressure. Patients with moderate to high risk of PONV should receive prophylactic antiemetic therapy (Table 40-5). For patients with moderate risk, prophylaxis with one or more agents is recommended; whereas for patients with high risk, combination prophylaxis with two to three agents from different classes is recommended.

Treatment of Postoperative Nausea and Vomiting

Patients who experience PONV and who have not received prophylaxis should be treated with a low-dose 5-HT3 receptor antagonist (dolasetron 12.5 mg, ondansetron 1 mg, granisetron 0.1 mg).20,21,23 If a patient has received dexamethasone prior to the procedure and experiences PONV, then a low-dose 5-HT3 receptor antagonist can be tried.20,21,23 When a 5-HT3 receptor antagonist is used, if PONV is experienced within 6 hours of initial administration, then a drug with a different mechanism of action should be used and the 5-HT3 antagonist dose should not be repeated.20,21 If a patient is still in post-anesthesia care, propofol, 20 mg as needed, can be used for PONV when a 5-HT3 receptor antagonist is given as initial prophylaxis.

Propofol may also be needed if initial triple antiemetic therapy fails. When PONV occurs more than 6 hours after the initial agent was given, any of these drugs can be used again for treatment of PONV.

• Nausea and vomiting are two of the most common side effects experienced by patients receiving chemotherapy.
• Various neurotransmitters are involved in the pathogenesis of nausea and vomiting, including dopamine, serotonin, histamine, and neurokinin-1.
• Risk factors for developing CINV include rate of infusion, dose of drug, younger patients, female patients, and those with a history of motion sickness or nausea with pregnancy.
• Acute and delayed CINV are easier to prevent than to treat. Antiemetic drug therapy should be directed toward the prevention of acute and delayed CINV.
• Serotonin (5-HT3) antagonists and dexamethasone should be used in the prevention, not treatment, of acute CINV.
• Aprepitant is useful in the prevention, not the treatment, of acute and delayed nausea and vomiting and should be used in highly emetogenic regimens, regimens at risk for delayed nausea, or for the combination of cyclophosphamide/doxorubicin.
• Dopamine antagonists such as promethazine are used in the treatment of breakthrough nausea and vomiting.
• When treating breakthrough CINV, a drug with a different mechanism of action than prescribed previously should be used.
• Benzodiazepines such as lorazepam are useful in the prevention of anticipatory CINV.
• Risk factors for developing PONV include type of anesthetic used, duration of surgery, type of surgery, female patients, nonsmokers, and history of PONV.
• Serotonin antagonists are the antiemetic class most often given for patients at high risk for PONV.