Pharmacotherapy A Pathophysiologic Approach, 9th Ed.

22. Nausea and Vomiting

Cecily V. DiPiro and Robert J. Ignoffo


KEY CONCEPTS

 Images Nausea and/or vomiting is often a part of the symptom complex for a variety of GI, cardiovascular, infectious, neurologic, metabolic, or psychogenic processes.

 Images Nausea or vomiting is caused by a variety of medications or other noxious agents.

 Images The overall goal of treatment should be to prevent or eliminate nausea and vomiting regardless of etiology.

 Images Treatment options for nausea and vomiting include drug and nondrug modalities such as relaxation, biofeedback, and self-hypnosis.

 Images The primary goal with chemotherapy-induced nausea and vomiting (CINV) is to prevent nausea and/or vomiting. Optimal control of acute nausea and vomiting positively impacts the incidence and control of delayed and anticipatory nausea and vomiting.

 Images The emetic risk of the chemotherapeutic regimen is the primary factor to consider when selecting prophylactic antiemetics for CINV.

 Images Patients at high risk of vomiting should receive prophylactic antiemetics for postoperative nausea and vomiting.

 Images Patients undergoing radiation therapy to the upper abdomen or receiving total or hemibody irradiation should receive prophylactic antiemetics for radiation-induced nausea and vomiting.


Nausea and vomiting are common complaints from individuals of all ages. Management can be quite simple or detailed and complex, essentially innocuous or associated with therapy-induced adverse reactions. This chapter provides an overview of nausea and vomiting, two multifaceted problems.

Nausea is defined as the inclination to vomit or as a feeling in the throat or epigastric region alerting an individual that vomiting is imminent. Vomiting is defined as the ejection or expulsion of gastric contents through the mouth and is often a forceful event. Either condition may occur transiently with no other associated signs or symptoms; however, these conditions also may be only part of a more complex clinical presentation.

ETIOLOGY

Images Nausea and vomiting may be associated with a variety of conditions, including GI, cardiovascular, infectious, neurologic, or metabolic disease processes. Nausea and vomiting may be a feature of such conditions as pregnancy, or may follow operative procedures or administration of certain medications, such as those used in cancer chemotherapy. Psychogenic etiologies of these symptoms may be present. Anticipatory etiologies may be involved, such as in patients who have previously received cytotoxic chemotherapy. Table 22-1 lists specific etiologies associated with nausea and vomiting.1

TABLE 22-1 Specific Etiologies of Nausea and Vomiting

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The etiology of nausea and vomiting may vary with the age of the patient. For example, vomiting in the newborn during the first day of life suggests upper digestive tract obstruction or an increase in intracranial pressure. ImagesDrug-induced nausea and vomiting are of particular concern, especially with the increasing number of patients receiving cytotoxic treatment. A four-level classification system defines the risk for emesis with agents used in oncology (Table 22-2).2 Although some agents may have greater emetic risk than others, combinations of agents, high doses, clinical settings, psychological conditions, prior treatment experiences, and unusual stimulus of sight, smell, or taste may alter a patient’s response to drug treatment. In this setting, nausea and vomiting may be unavoidable and some patients experience these problems so intensely that chemotherapy is postponed or discontinued.

TABLE 22-2 Emetic Risk of Agents Used in Oncology

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PATHOPHYSIOLOGY

The three consecutive phases of emesis include nausea, retching, and vomiting. Nausea, the imminent need to vomit, is associated with gastric stasis and may be considered a separate and singular symptom. Retching is the labored movement of abdominal and thoracic muscles before vomiting. The final phase of emesis is vomiting, the forceful expulsion of gastric contents caused by GI retroperistalsis. The act of vomiting requires the coordinated contractions of the abdominal muscles, pylorus, and antrum, a raised gastric cardia, diminished lower esophageal sphincter pressure, and esophageal dilation.1 Vomiting should not be confused with regurgitation, an act in which the gastric or esophageal contents rise to the pharynx but is not usually associated with forceful ejection seen with vomiting. Accompanying autonomic symptoms of pallor, tachycardia, and diaphoresis account for many of the distressing feelings associated with emesis.

Vomiting is triggered by afferent impulses to the vomiting center, a nucleus of cells in the medulla. Impulses are received from sensory centers, which include the chemoreceptor trigger zone (CTZ), cerebral cortex, and visceral afferents from the pharynx and GI tract. The vomiting center integrates the afferent impulses, resulting in efferent impulses to the salivation center, respiratory center, and the pharyngeal, GI, and abdominal muscles, leading to vomiting.

The CTZ, located in the area postrema of the fourth ventricle of the brain, is a major chemosensory organ for emesis and is usually associated with chemically induced vomiting. Because of its location, bloodborne and cerebrospinal fluid toxins have easy access to the CTZ. Cytotoxic agents primarily stimulate this area rather than the cerebral cortex and visceral afferents. Similarly, pregnancy-associated vomiting probably occurs through stimulation of the CTZ.

Numerous neurotransmitter receptors are located in the vomiting center, CTZ, and GI tract, including cholinergic, histaminic, dopaminergic, opiate, serotonergic, neurokinin (NK), and benzodiazepine receptors. Chemotherapeutic agents, their metabolites, or other emetic compounds theoretically trigger the process of emesis through stimulation of one or more of these receptors. Antiemetics have been developed to antagonize or block these emetogenic receptors.

CLINICAL PRESENTATION

Nausea and vomiting are commonly seen in many clinical situations. Patients may present in varying degrees of distress summarized in Table 22-3 as simple or complex in presentation.

TABLE 22-3 Clinical Presentation of Nausea and Vomiting

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TREATMENT

Desired Outcome

Images The overall goal of antiemetic therapy is to prevent or eliminate nausea and vomiting. This should be accomplished without adverse effects or with clinically acceptable adverse effects. Although this goal may be accomplished easily in patients with simple nausea and vomiting, patients with more complex problems require greater assistance. In addition to these clinical goals, appropriate cost issues should be considered, particularly in the management of chemotherapy-induced nausea and vomiting (CINV) and postoperative nausea and vomiting (PONV).

General Approach to Treatment

Images Treatment options include drug and nondrug modalities. Initially patients may choose to do nothing or to self-medicate with nonprescription drugs. As symptoms become worse or are associated with more serious medical problems, patients are more likely to benefit from prescription antiemetic drugs. When prescribed according to reliable clinical information, these agents often provide acceptable relief; however, some patients will never be totally free of symptoms. This lack of relief is most disabling when it is associated with an unresolved medical problem or when the necessary therapy for this condition is the cause of the nausea or vomiting, as in the case of patients who are receiving chemotherapy of moderate or high emetic risk.

Nonpharmacologic Management

Nonpharmacologic management of nausea and vomiting involves dietary, physical, or psychological strategies that are consistent with the etiology of nausea and vomiting. For patients with simple complaints, perhaps resulting from excessive or disagreeable food or beverage consumption, avoidance or moderation in dietary intake may be preferable. Patients suffering symptoms of systemic illness may improve dramatically as their underlying condition resolves. Finally, patients in whom these symptoms result from labyrinthine changes produced by motion may benefit quickly by assuming a stable physical position.

Nonpharmacologic interventions are classified as behavioral interventions and include relaxation, biofeedback, self-hypnosis, cognitive distraction, guided imagery, acupuncture, and systematic desensitization.3,4 The reader is referred to references 5 to 7 for a more complete discussion on nonpharmacologic strategies.

Pharmacologic Therapy

Images Although many approaches to the treatment of nausea and vomiting have been suggested, antiemetic drugs (nonprescription and prescription) are most often recommended. These agents represent a variety of pharmacologic and chemical classes, as well as dosage regimens and routes of administration. With so many treatment possibilities available, factors that enable the clinician to discriminate among various choices include (a) the suspected etiology of the symptoms; (b) the frequency, duration, and severity of the episodes; (c) the ability of the patient to use oral, rectal, injectable, or transdermal medications; and (d) the success of previous antiemetic medications. Please see Table 22-4 for dosing information of commonly available antiemetic preparations.

TABLE 22-4 Common Antiemetic Preparations and Adult Dosage Regimens

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The treatment of simple nausea and vomiting often involves self-care from a lengthy list of nonprescription products. Both nonprescription and prescription drugs useful in the treatment of simple nausea and vomiting are usually effective in small, infrequently administered doses associated with minimal side effects. Although suitable for occasional simple nausea and vomiting, nonprescription agents are often abandoned by the patient as symptoms continue or become progressively worse. As the patient’s condition warrants, prescription medications may be chosen, either as single-agent therapy or in combination.

The management of complex nausea and vomiting, for example, in patients who are receiving cytotoxic chemotherapy, may require combination therapy. In combination regimens, the goal is to achieve symptomatic control through administration of agents with different pharmacologic mechanisms of action.

Antacids

Patients who are experiencing simple nausea and vomiting may use various antacids. In this setting, single or combination nonprescription antacid products, especially those containing magnesium hydroxide, aluminum hydroxide, and/or calcium carbonate, may provide sufficient relief, primarily through gastric acid neutralization.

Antihistamine–Anticholinergic Drugs

Antiemetic drugs from the antihistaminic–anticholinergic category appear to interrupt various visceral afferent pathways that stimulate nausea and vomiting. These drugs are often initiated as self-care by the patient for simple nausea or vomiting, especially associated with motion sickness.

Benzodiazepines

Since nausea and vomiting are often associated with chemotherapy, radiotherapy, and surgery, anticipatory anxiety may occur prior to these therapies and may exacerbate symptoms. Benzodiazepines may be useful in this setting.

Benzodiazepines are relatively weak antiemetics and are primarily used to prevent anxiety or anticipatory nausea and vomiting (ANV) in patients receiving highly emetogenic chemotherapy. They are also useful against akathisia associated with metoclopramide therapy. Both alprazolam and lorazepam are used as adjuncts to other antiemetics in patients treated with cisplatin-containing regimens. Alprazolam is usually given orally and has an onset of about 60 minutes, while lorazepam is given orally or sublingually, which has a more rapid onset.

Butyrophenones

Two butyrophenone compounds that have antiemetic activity are haloperidol and its congener droperidol; both block dopaminergic stimulation of the CTZ. Although each agent is effective in relieving nausea and vomiting, haloperidol is not considered first-line therapy for uncomplicated nausea and vomiting but has been used in palliative care situations.8 The current labeling of droperidol recommends that all patients should undergo a 12-lead electrocardiogram prior to administration, followed by cardiac monitoring for 2 to 3 hours after administration because of the possibility of the development of potentially fatal QT prolongation and/or torsade de pointes.9 The clinical use of droperidol has effectively ceased outside of clinical trials in anesthesia.

Cannabinoids

Cannabinoids have complex effects on the CNS and their effects at receptors in neural tissues may explain efficacy in CINV. Oral dronabinol and nabilone are therapeutic options when CINV is refractory to other antiemetics; they are not indicated as first-line agents.10

Corticosteroids

Corticosteroids have demonstrated antiemetic efficacy since the initial recognition that patients who received prednisone as part of their Hodgkin’s disease protocol appeared to develop less nausea and vomiting than did those patients who were treated with protocols that excluded this agent. Methylprednisolone has also been used as a component of an antiemetic regimen, but the majority of trials have included dexamethasone. The site and mechanism of action of corticosteroids for CINV is unknown.

Dexamethasone is the most commonly used corticosteroid in the management of CINV and PONV, either as a single agent or in combination with 5-hydroxytryptamine-3 receptor antagonists (5-HT3-RA). Dexamethasone is effective in the prevention of both cisplatin-induced acute emesis and delayed nausea and vomiting associated with CINV when used alone or in combination.1114 Corticosteroids affect almost every organ system. For patients with simple nausea and vomiting, steroids are not indicated and may be associated with unacceptable risks.

H2-Receptor Antagonists

Histamine2-receptor antagonists work by decreasing gastric acid production and are used to manage simple nausea and vomiting associated with heartburn or gastroesophageal reflux. Except for potential drug interactions with cimetidine, these agents cause few side effects when used for episodic relief.

5-Hydroxytryptamine-3 Receptor Antagonists

5-HT3-RAs block presynaptic serotonin receptors on sensory vagal fibers in the gut wall, effectively blocking the acute phase of CINV. These agents do not completely block the acute phase of CINV and are less efficacious in preventing the delayed phase, but they are the standard of care in the management of CINV, PONV, and radiation-induced nausea and vomiting (RINV). Issues involved in the use of dolasetron, granisetron, ondansetron, and palonosetron are reviewed in detail in the sections that follow.

Metoclopramide

Metoclopramide, a procainamide congener, blocks dopaminergic receptors centrally in the CTZ. It increases lower esophageal sphincter tone, aids gastric emptying, and accelerates transit through the small bowel, possibly through the release of acetylcholine. The prokinetic activity of metoclopramide makes it useful in patients with nausea and vomiting associated with diabetic gastroparesis. The introduction of the 5-HT3-RAs in the early 1990s supplanted the use of metoclopramide in CINV.

Olanzapine

Olanzapine is an antipsychotic that blocks several neurotransmitters including dopamine at D2 and 5-HT3-RA. Use of olanzapine, in combination with palonosetron and dexamethasone, effectively controlled acute and delayed CINV in patients receiving highly emetogenic chemotherapy as compared with aprepitant, palonosetron, and dexamethasone in a randomized, phase 3 clinical trial.15 The National Comprehensive Cancer Network (NCCN) antiemesis practice guideline includes olanzapine as one of many options in patients who experience breakthrough nausea and/or vomiting following prophylaxis for CINV.16 Sedation is the most common side effect with olanzapine; it should be used with caution in the elderly.

Phenothiazines

Phenothiazines have been the most widely prescribed antiemetic agents and appear to block dopamine receptors, most likely in the CTZ. They are marketed in an array of dosage forms, none of which appears to be more efficacious than another. These agents may be most practical for long-term treatment and are inexpensive in comparison with newer drugs. Rectal administration is a reasonable alternative in patients in whom oral or parenteral administration is not feasible.

Phenothiazines are most useful in adult patients with simple nausea and vomiting. IV prochlorperazine provided quicker and more complete relief with less drowsiness than IV promethazine in adult patients treated in an emergency department for nausea and vomiting associated with uncomplicated gastritis or gastroenteritis.17

Substance P/Neurokinin 1 Receptor Antagonists

Substance P is a peptide neurotransmitter in the NK family whose preferred receptor is the NK1 receptor. The acute phase of CINV is believed to be mediated by both serotonin and substance P, whereas substance P is believed to be the primary mediator of the delayed phase. Aprepitant and fosaprepitant are the first substance P/NK1 receptor antagonists in clinical use; at the time of this writing, casopitant is still in development.

The efficacy of aprepitant was demonstrated in patients receiving high-dose cisplatin-based chemotherapy13,14 and in patients receiving doxorubicin and cyclophosphamide,18 a regimen of moderate to high emetic risk. The three-drug regimen of aprepitant, dexamethasone, and ondansetron provided improved protection from vomiting for the 5 days after chemotherapy administration as compared with the combination of dexamethasone and ondansetron.

Aprepitant has the potential for numerous drug interactions because it is a substrate, moderate inhibitor, and an inducer of cytochrome isoenzyme CYP3A4 and an inducer of CYP2C9. It can increase serum concentrations of many drugs metabolized by CYP3A4, including docetaxel, paclitaxel, etoposide, irinotecan, ifosfamide, imatinib, vinorelbine, vincristine, and vinblastine. In clinical studies, aprepitant was concomitantly administered with etoposide, vinorelbine, or paclitaxel, with no adjustment in the doses of these agents to account for potential drug interactions. The efficacy of oral contraceptives may be reduced when given with aprepitant. Concomitant administration with warfarin may result in a clinically significant decrease in the international normalized ratio.19 The dose of oral dexamethasone should be reduced 50% when coadministered with aprepitant, because of the 2.2-fold increase in observed area under the plasma-concentration-versus-time curve.20 Aprepitant is not approved for use in children.

Fosaprepitant, an injectable form of aprepitant, has been approved by the FDA as an IV substitute for oral aprepitant on day 1 of the standard 3-day CINV prevention regimen, with oral aprepitant administered on days 2 and 3.21

CHEMOTHERAPY-INDUCED NAUSEA AND VOMITING

There are five categories of CINV: acute, delayed, anticipatory, breakthrough, and refractory. Nausea and vomiting that occurs within 24 hours of chemotherapy administration is defined as acute CINV, whereas when it starts more than 24 hours after chemotherapy administration, it is defined as delayed CINV.

Nausea or vomiting that occurs prior to receiving chemotherapy is termed ANV. ANV is believed to be a learned, conditioned, or psychological response that occurs in about 25% of patients by the fourth cycle of chemotherapy.22ANV triggers include tastes, odors, sights, or thoughts associated with chemotherapy. Risk factors associated with ANV include age under 50, nausea and/or vomiting after the previous chemotherapy session, anxiety, sweating and a feeling of warmth after the last chemotherapy cycle, and susceptibility to motion sickness.23

In the setting of optimal antiemetic prophylaxis and no prior emesis, reported chemotherapy-induced ANV is rare. Use of newer antiemetic regimens appears to have resulted in a decreased rate of ANV.24

Breakthrough nausea and vomiting is defined as emesis occurring despite prophylactic administration of antiemetics and requiring the use of rescue antiemetics. Historically, breakthrough emesis occurs in 10% to 40% treated with modern-day antiemetics.25

Refractory nausea and vomiting is evident when there is a poor response to multiple antiemetic regimens. In addition to the emetic risk of various cytotoxic regimens, other common etiologies have been proposed for the development of nausea and vomiting in cancer patients (Table 22-5).26

TABLE 22-5 Nonchemotherapy Etiologies of Nausea and Vomiting in Cancer Patients

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Images The primary goal for CINV is to prevent nausea and/or vomiting. Optimal control of acute nausea and vomiting is known to impact positively on the incidence and control of delayed nausea and vomiting and ANV.25

Clinical practice guidelines for the use of antiemetics in CINV have been published by the NCCN,16 the Multinational Association of Supportive Care in Cancer/European Society of Oncology (MASCC/ESMO),24 and the American Society of Clinical Oncology (ASCO).27 The NCCN guidelines are updated annually, while the ASCO and ESMO guidelines appear to be updated less frequently. Despite the demonstrated improvement in outcomes with the use of these practice guidelines, they are underutilized by a high percentage of practitioners.28 Furthermore, product availability and recommended doses are often institution-specific and may vary considerably from the doses listed in Table 22-6.

TABLE 22-6 Dosage Recommendations for CINV for Adult Patients

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Principles of Antiemetic Use for CINV

ASCO, MASCC, and the NCCN consensus groups share several of the principles listed below that appear to be important for the effective prevention of CINV in adults29,30:

   1. The primary goal of emesis prevention is no nausea and/or vomiting throughout the period of emetic risk.

   2. The duration of emetic risk is 2 days for patients receiving moderately emetogenic chemotherapy and 3 days for highly emetogenic chemotherapy. Emetic prophylaxis should be provided through the entire period of risk.

   3. Images The selection of the antiemetic regimen should be based on the chemotherapy drug with highest emetogenicity (see Table 22-2). Prior emetic experience and patient-specific factors should also be considered.

   4. When given in equipotent doses, oral and IV 5-HT3-RAs are equivalent in efficacy.

   5. The toxicities of antiemetics should be considered and managed appropriately.

Prophylaxis of Acute CINV

Each of the practice guidelines states that the most effective classes of drugs for the prevention of acute emesis are the 5-HT3-RAs, NK1 receptor antagonists, and glucocorticoids (especially dexamethasone). Treatment recommendations for the different categories of emesis are outlined in Table 22-6.

High Emetogenic Chemotherapy (HEC)

Patients receiving HEC should receive a three-drug antiemetic regimen given before the administration of chemotherapy (day 1) that includes a 5-HT3-RA (e.g., dolasetron, granisetron, ondansetron, or palonosetron), dexamethasone, and an NK1 receptor antagonist (e.g., aprepitant or fosaprepitant). Dexamethasone should be given on days 2 to 4 and aprepitant on days 2 and 3 to prevent delayed emesis.

Any of the 5-HT3-RAs may be used on day 1. The ASCO and NCCN guidelines prefer IV palonosetron. The use of IV dolasetron is contraindicated because it has a higher association of prolonged QTcinterval. Granisetron transdermal patch should be applied 24 to 48 hours prior to chemotherapy (duration of effect is 7 days).


Clinical Controversy…

Is triple therapy necessary in all patients receiving HEC? The major guidelines all recommend that a combination of a corticosteroid, a 5-HT3-RA, and aprepitant should be standard prophylaxis for HEC-associated vomiting. The data raise some doubt about whether all anthracycline and cyclophosphamide chemotherapy and dacarbazine regimens require an NK1 receptor antagonist at least when palonosetron is used. Few studies have carefully evaluated the risk of emesis with any chemotherapy other than cisplatin or anthracycline and cyclophosphamide in women.31

Moderate Emetogenic Chemotherapy (MEC)

Patients receiving MEC should receive a two-drug antiemetic regimen containing a 5-HT3-RA on day 1 and dexamethasone on days 1 to 3. Both ASCO and NCCN guidelines recommend palonosetron as the preferred 5-HT3-RA for MEC. The exception to this is patients who are receiving combination chemotherapies with carboplatin, cisplatin, doxorubicin, epirubicin, ifosfamide, irinotecan, or methotrexate; these patients may be given the triple-drug combination described for regimens of high emetic risk.

For chemotherapy regimens that are of low emetic risk, dexamethasone or any of the following may be used: prochlorperazine, metoclopramide, and/or diphenhydramine, and/or lorazepam alone.16

Prophylaxis of Delayed CINV

Management of delayed CINV has historically challenged practitioners. The best strategy for preventing delayed CINV (nausea and/or vomiting occurring 24 or more hours after chemotherapy) is to control acute CINV and provide adequate prophylaxis for delayed CINV.32 Aprepitant, dexamethasone, and metoclopramide are effective in preventing delayed CINV, whereas 5-HT3-RAs are inconsistent. However, palonosetron controlled delayed emesis more effectively than granisetron, suggesting that another 5-HT3-RA should not be prescribed as a rescue medication when palonosetron is given prophylactically for acute CINV.33

Patients receiving cisplatin and other HEC regimens are at highest risk for experiencing delayed CINV. The combination of aprepitant and dexamethasone on days 2 and 3 appears to be superior to the use of dexamethasone alone or ondansetron plus dexamethasone in preventing delayed emesis.34 Use of aprepitant also decreased delayed CINV in patients receiving an anthracycline plus cyclophosphamide, as compared with twice-daily ondansetron (49% vs. 55%).18 Fosaprepitant, a parenteral formulation of aprepitant, given on day 1 plus dexamethasone on days 1 to 4 was effective for prevention of both acute and delayed emesis from cisplatin therapy.35 Current practice guidelines recommend administration of aprepitant and dexamethasone on days 2 and 3 and dexamethasone with or without lorazepam on day 4.16,24

The incidence of delayed CINV following MEC is less well defined. The NCCN recommends aprepitant or any of the following: dexamethasone, a 5-HT3-RA, and/or lorazepam, and/or a histamine2-blocker, or a proton pump inhibitor on days 2 and 3 for chemotherapy regimens that contain carboplatin, doxorubicin, epirubicin, ifosfamide, irinotecan, or methotrexate.16 In contrast, the ASCO guidelines do not recommend aprepitant for MEC.27

Palonosetron protected more patients from delayed emesis than ondansetron, granisetron, or dolasetron in adult patients receiving MEC.3639 Although these studies showed that palonosetron is superior to other 5-HT3-RAs, it is unclear whether these results would persist if an NK1 antagonist were included in the combination. Palonosetron may also be better than ondansetron in patients receiving multiday chemotherapy, but a larger randomized, prospective trial is needed to substantiate this finding.40

Prophylaxis of Anticipatory Nausea and Vomiting

The 2009 update of the MASCC antiemetic guidelines for preventing ANV stated that although there was only a moderate level of confidence, there was a high level of consensus for using a benzodiazepine combined with standard antiemetics for preventing ANV.22 Alprazolam or lorazepam given the night before and the morning of chemotherapy is recommended.

Treatment of Anticipatory Nausea and Vomiting

ANV is more difficult to control than acute or delayed CINV. A key principle in the treatment of ANV is that effective management of delayed CINV or ANV requires adequate control of acute CINV. The most effective treatment for prevention of ANV is to give optimal antiemetic prophylaxis with each cycle of chemotherapy.41

Treatment of Breakthrough CINV

A general principle in all patients receiving chemotherapy is to prescribe an antiemetic from a different pharmacologic class for rescue of breakthrough nausea and vomiting. Rescue medications used in adult patients include prochlorperazine, promethazine, lorazepam, metoclopramide, haloperidol, 5-HT3-RAs, dexamethasone, cannabinoids, or olanzapine.16,42

Around-the-clock dosing of rescue antiemetics should be considered rather than as-needed administration. The choice of agent should be based on patient-specific factors, including potential adverse drug reactions and cost. Chlorpromazine, lorazepam, and dexamethasone are recommended for pediatric patients.43

Treatment of Refractory Nausea and Vomiting

The general approach to the management of refractory CINV is to upgrade the antiemetic strategy to the next level of prophylaxis or to add breakthrough antiemetics to the regimen.44 Some patients will experience nausea and vomiting despite optimal acute and delayed prophylaxis and failure of rescue antiemetics. Addition of another agent from a different pharmacologic class is recommended and routes other than the oral route may be required.

Treatment of Multiday Chemotherapy

Chemotherapy regimens are occasionally administered over multiple days. The MASCC guidelines state that the combination of a 5-HT3-RA plus daily dexamethasone is the standard.24 For highly emetogenic regimens, dexamethasone should be administered daily on the days of chemotherapy. Dexamethasone should not be prescribed for patients receiving a corticosteroid in their chemotherapy regimen or with interferon alfa or interleukin-2.30 The use of a 5-HT3-RA daily or granisetron transdermal patch plus daily dexamethasone and either aprepitant has been recommended on days 1 to 3, or fosaprepitant on day 1.36

POSTOPERATIVE NAUSEA AND VOMITING

PONV in adults occurs in 25% to 30% of patients and within 24 hours of undergoing anesthesia.45 Patients with multiple risk factors are at highest risk for PONV (Table 22-7). Patients with zero or one of the four risk factors present in Table 22-7 are at lowest risk (10% to 20%) and those with three or four risk factors are at highest risk for PONV (60% to 80%). Moderate risk is defined by this model as the presence of two risk factors. Patients at low risk for PONV are unlikely to benefit from prophylaxis and may potentially experience adverse reactions from the medications. The use of a risk assessment tool can help identify patients most likely to benefit from prophylaxis.46

TABLE 22-7 Risk Factors for Postoperative Nausea and Vomiting (PONV)

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In addition to using prophylactic antiemetics in high-risk patients, other strategies include using regional rather than systemic anesthesia, propofol, and hydration, as well as avoiding nitrous oxide, volatile anesthetics, and opioids.

Prophylaxis of PONV

Adherence to consensus guidelines for prophylaxis and treatment of PONV decreases emetic episodes.47,48Images Patients at highest risk of vomiting should receive two prophylactic antiemetics from different pharmacologic classes, while those at moderate risk should receive one or two drugs.47,49 Optimal outcomes appear to be achieved when the drugs are administered at the end of the surgery. When the different combinations were compared, no differences were found between 5-HT3-RA plus droperidol, 5-HT3-RA plus dexamethasone, and droperidol plus dexamethasone.50 However, QT prolongation and/or torsade de pointes has been reported in some cases, with some fatalities in patients receiving droperidol at doses at or below recommended doses. Droperidol should be avoided in patients who have a history of QT prolongation, are over 65 years old, or have a history of alcohol abuse, or when used concomitantly with benzodiazepines, volatile anesthetics, and IV opiates.9 Optimal dosing of agents used in combination has not been determined.

Cyclizine, dexamethasone, dolasetron, droperidol, granisetron, metoclopramide, ondansetron, tropisetron, scopolamine, and palonosetron are as effective as placebo for the prophylaxis of PONV.5153Acquisition cost may be the primary factor that determines drug selection of the 5-HT3-RAs.47 Dexamethasone is an effective, inexpensive prophylactic agent when administered either alone or in combination with other antiemetic drugs before the induction of anesthesia.49,51 Table 22-8 summarizes the doses for prophylactic antiemetics from the consensus guidelines.47

TABLE 22-8 Recommended Prophylactic Doses of Selected Antiemetics for Postoperative Nausea and Vomiting in Adults and Postoperative Vomiting in Children

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Aprepitant was approved for the prevention of PONV given orally within 3 hours prior to induction of anesthesia.19 Aprepitant is equivalent to ondansetron 4 mg IV in reducing the incidence of nausea and the need for rescue in the 24 hours after surgery, but was significantly better than ondansetron for preventing vomiting in the 24 and 48 hours after surgery.54


Clinical Controversy…

When should droperidol be used for prophylaxis of PONV? Several clinical practice guidelines include droperidol as a first-line agent in the prevention of nausea and vomiting in high-risk patients receiving preoperative anesthesia. The black box warning in the product information recommends that this drug be reserved for patients who cannot tolerate or do not respond to other agents. This has led to debate and controversy in the literature as to the role of droperidol for PONV.55,56

Treatment of PONV

Patients who experience PONV after receiving prophylactic treatment with a 5-HT3-RA plus dexamethasone should be given rescue therapy from a different drug class such as a phenothiazine, metoclopramide, or droperidol.47Repeating the agent given for PONV prophylaxis within 6 hours of surgery is of no additional benefit.57 Furthermore, a repeated dose of a 5-HT3-RA is not effective in treatment of PONV.58,59 An emetic episode occurring more than 6 hours postoperatively can be treated with any of the drugs used for prophylaxis except dexamethasone and transdermal scopolamine.47

If no prophylaxis was given initially, the recommended treatment is low-dose 5-HT3-RA as follows: dolasetron 12.5 mg, granisetron 0.1 mg, ondansetron 1 mg, and tropisetron 0.5 mg. Alternative treatments for established PONV include dexamethasone 2 to 4 mg IV, droperidol 0.625 mg IV, or promethazine 6.25 to 12.5 mg IV.60

RADIATION-INDUCED NAUSEA AND VOMITING

Nausea and vomiting associated with radiation therapy (RT) is not well understood and often underestimated by radiation oncologists.61 RINV is neither as predictable nor as severe as CINV, and many patients receiving RT will not experience nausea or vomiting. The incidence of RINV ranges from 50% to 80%, is site dependent, and can have a substantial impact on a patient’s quality of life. Risk factors associated with the development of RINV include combination chemoradiotherapy, prior CINV, upper abdomen RT, and field size.62

Four radiotherapy-induced emesis risk groups have been defined by the Antiemetic Subcommittee of the MASCC and the ASCO antiemetic practice guidelines24,27:

   1. Highest risk: Total-body or nodal irradiation (TBI/TNI)

   2. Moderate risk: Upper body or abdomen and hemibody RT

   3. Low risk: Cranial, craniospinal, head and neck, lower thorax, and pelvic RT

   4. Minimal risk: Extremity or breast RT

Prophylaxis of RINV

Images Several randomized trials have demonstrated that prophylactic 5-HT3-RA and dexamethasone are more effective than placebo,62 which was confirmed by a recent meta-analysis.63 In addition, 5-HT3-RAs were more effective than placebo or non-5-HT3-RAs (prochlorperazine or metoclopramide), even in patients undergoing TBI.62

ASCO, ESMO/MASCC, and NCCN recommend preventive therapy with a 5-HT3-RA throughout RT and dexamethasone on fractions 1 to 5 in patients who are receiving TBI (high emetic risk).16,27,61Patients undergoing RT procedures with moderate emetic risk should receive a 5-HT3-RA prior to each fraction and dexamethasone on fractions 1 to 5. Those receiving low emetic risk radiotherapy may be given a 5-HT3-RA either throughout RT or as rescue. For minimal emetic risk a 5-HT3-RA, metoclopramide, or prochlorperazine may be offered.

There has not been adequate study of prophylactic NK1 antagonists, palonosetron, or transdermal granisetron in the setting of RINV.

DISORDERS OF BALANCE

Disorders of balance include vertigo, dizziness, and motion sickness. The etiology of these complaints may include diseases that are infectious, postinfectious, demyelinative, vascular, neoplastic, degenerative, traumatic, toxic, psychogenic, or idiopathic. Symptoms of imbalance perceived by the patient present a particular clinical challenge. Whether associated with a minor or complex disorder, motion sickness may be associated with nausea and vomiting.

Beneficial therapy for patients in this setting can most reliably be found among the antihistaminic–anticholinergic agents. However, the precise mechanisms of action of these agents are currently unknown. Neither the antihistaminic nor the anticholinergic potency appears to correlate well with the ability of these agents to prevent or treat the nausea and vomiting associated with motion sickness. When used for their depressant effects on labyrinth excitability, these agents produce variable efficacy and safety profiles. Oral regimens of antihistaminic–anticholinergic agents given one to several times each day may be effective, especially when the first dose is administered prior to motion.

Scopolamine is commonly used to prevent nausea or vomiting caused by motion. The usefulness of scopolamine in preventing motion sickness was enhanced with the development of the transdermal system (patch) that increased patient satisfaction and decreased untoward side effects. A review of 12 randomized controlled studies showed that scopolamine provided better protection from motion-induced sickness than did placebo, but was not superior to antihistamines and combinations of scopolamine and ephedrine.64

ANTIEMETIC USE DURING PREGNANCY

As many as 75% of pregnant women experience nausea and vomiting to some degree during the first trimester of pregnancy. The severity of the symptoms varies considerably, from mild nausea to incapacitating nausea and vomiting. The etiology of nausea and vomiting of pregnancy (NVP) is not well understood. Symptoms are self-limited for a majority of women, although approximately 1% to 3% develop hyperemesis gravidarum, a serious condition marked by severe physical symptoms and/or medical complications requiring hospitalization. In its most severe state, hyperemesis gravidarum may result in volume contraction, starvation, and electrolyte abnormalities.

Initial management of NVP often involves dietary changes and/or lifestyle modifications. Nonpharmacologic interventions including ginger and acupressure are not supported by high-quality consistent evidence.65 Persistent nausea and/or vomiting leads to the consideration of drug therapy at a time when teratogenic potential of each agent must be considered.

Treatment recommendations for the management of NVP are available from the American College of Obstetricians and Gynecologists (ACOG).66 A comprehensive review of treatment options for NVP was published.67Pyridoxine (10 to 25 mg one to four times daily), with or without doxylamine (12.5 to 20 mg one to four times daily), is recommended as first-line therapy.

Patients with persistent NVP or who show signs of dehydration should receive IV fluid replacement with thiamine. Ondansetron 2 to 8 mg orally/IV every 8 hours as needed may alleviate NVP, but IV ondansetron was no more effective than promethazine for treatment of severe NVP.68 Corticosteroids should be reserved for patients with refractory NVP or hyperemesis gravidarum; methylprednisolone 16 mg orally/IV every 8 hours for 3 days followed by a 2-week taper is recommended. This regimen may be repeated if necessary, but treatment should not exceed a total of 6 weeks.

ANTIEMETIC USE IN CHILDREN

Chemotherapy-Induced Nausea and Vomiting

Updated practice guidelines recommend that a corticosteroid (such as dexamethasone) plus a 5-HT3-RA be administered as prophylaxis of acute CINV to children receiving chemotherapy of high or moderate emetic risk.69Consensus guidelines suggest that there are no differences between 5-HT3-RAs in safety or efficacy. One small, randomized, comparative study demonstrated that one dose of palonosetron 0.25 mg IV significantly reduced emesis and nausea in the first 3 days as compared with ondansetron (8 mg/m2 IV every 8 hours while receiving chemotherapy) in children treated with moderately to highly emetogenic chemotherapy.70 This study needs to be confirmed in a larger randomized trial.

One small study has evaluated the safety and efficacy of aprepitant in adolescents. Patients were randomized to dexamethasone and ondansetron with or without aprepitant, using the recommended oral adult 3-day regimen. The emetogenicity of the chemotherapy administered was not discussed. Patients in the aprepitant arm had higher complete response rates and a parallel pharmacokinetic study suggests that the adult dose regimen was appropriate for adolescents.71

Gastroenteritis

Nausea and vomiting associated with pediatric gastroenteritis is self-limited and improves with correction of dehydration. The majority of patients can be successfully treated with oral rehydration therapy (ORT). Use of phenothiazines, such as promethazine, has declined due to potential serious adverse events in children and adolescents, including death.72 Administration of a single dose of ondansetron appears to decrease persistent vomiting as a barrier to ORT and decreases need for IV rehydration and hospital admission.7375

PERSONALIZED PHARMACOTHERAPY

Antiemetics are 70% to 80% effective in the prevention of CINV. One potential factor that might explain less than optimal response is the variability in genetic enzymes responsible for the metabolism, transport, and receptor affinity of antiemetics.76 The literature on the pharmacogenetics of antiemetic drugs is limited regarding the impact of the polymorphic variability in the multidrug resistance gene (MDR1), the 5-HT3-RA A, B, and C receptor genes, and the CYP2D6 gene on the efficacy of the 5-HT3-RAs. Individuals who are ultrametabolizers of the CYP2D6 enzymes generally respond poorly to 5-HT3-RAs and dopamine D2 receptor antagonists (prochloperazine and metoclopramide).77 Variant genotypes in the 5-HT3-RA C gene appear to invoke resistance to ondansetron and tropisetron and were associated with an increased risk of nausea and vomiting.78 In another study, complete antiemetic control was greater in patients with the TT genotype of the MDR1 compared with that in patients with the TC or CC genotype.79 Until there are confirmatory studies of these results, it is premature to utilize genomic analysis for personalized clinical decision making for use of 5-HT3-RAs.

With regard to the effect of pharmacokinetics on drug efficacy in PONV, clinical studies suggest that palonosetron is more effective against delayed emesis than other 5-HT3-RAs because of its higher receptor binding affinity and longer plasma elimination half-life.80 However, these studies were not compared with dexamethasone as part of the regimen. Although all the 5-HT3-RAs are hepatically metabolized and excreted in the urine, renal and hepatic dysfunction does not require dose adjustment.

EVALUATION OF EMETIC OUTCOMES

In assessing emetic outcomes, standardized monitoring criteria should include a subjective assessment and objectives parameters including:

   1. Severity of nausea

   2. Change in patient weight

   3. Number of vomiting episodes each day

   4. Estimated fluid loss

   5. Acid–base balance

   6. Serum sodium, potassium, and chloride concentrations

   7. Serum BUN and creatinine concentrations

   8. Daily urine volume and urine-specific gravity

Physical assessment should include evaluation of mucous membranes and skin turgor. For patients on chemotherapy, evaluation of emetic outcomes should occur after the administration of each chemotherapy cycle. Adherence to outpatient antiemetic regimens occurs in about 65% of patients. Delayed nausea and vomiting occurs in 15% to 40% of patients, depending on the emetic risk of the chemotherapy and the antiemetic regimen used for prophylaxis. Patients receiving high-risk regimens are most likely to report symptoms of nausea and vomiting on day 3 after chemotherapy.81 Symptom management assessments should be performed on the third or fourth day after chemotherapy. Documentation of a nausea and/or vomiting event will assist the clinician in modifying the antiemetic regimen for the next cycle of chemotherapy.

In the postsurgical anesthesia setting, assessment of nausea and vomiting is important since they may lead to dehydration, decreased blood pressure, or cardiac arrhythmias. Other complications of PONV include suture line tension, wound dehiscence, and increased bleeding under surgical flaps.82

ABBREVIATIONS

Images

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