Assessment and management of nausea and vomiting in palliative care

INTRODUCTION — Nausea and vomiting are common symptoms near the end of life that can cause substantial physical and psychological distress for patients and their families and significantly impact quality of life. Nausea, the sensation of being about to vomit, can occur alone or can accompany vomiting, dyspepsia, or other gastrointestinal symptoms. Vomiting is the expulsion of gastric contents through the mouth caused by forceful and sustained contraction of the abdominal muscles and diaphragm. In contrast to vomiting, retching does not involve the expulsion of gastric contents.

There are many potential causes of nausea and vomiting in palliative care patients, and the etiology is often multifactorial, particularly in patients with cancer. This topic review will cover the prevalence, etiology/pathophysiology, assessment, and management of nausea and vomiting in palliative care populations. Prevention and treatment of chemotherapy- and radiotherapy-induced nausea and vomiting (CINV and RINV) are covered in detail elsewhere. (See "Prevention of chemotherapy-induced nausea and vomiting in adults" and "Pathophysiology and prediction of chemotherapy-induced nausea and vomiting" and "Radiotherapy-induced nausea and vomiting: Prophylaxis and treatment" and "Management of poorly controlled or breakthrough chemotherapy-induced nausea and vomiting in adults".)

PATHOPHYSIOLOGIC PATHWAYS — In palliative care patients, symptoms of nausea and vomiting are often multifactorial. Common causes of nausea in patients in the palliative care setting are listed in the table (table 1). Identifying the underlying cause(s) may be useful for selecting a therapeutic option, especially for patients with cancer, who may have chemotherapy- or radiotherapy-induced nausea and vomiting (CINV and RINV), or malignant bowel obstruction (MBO).

The mechanisms producing vomiting and those causing nausea are distinct. Vomiting is not merely a more severe degree of nausea, since the neural circuits responsible for nausea appear to be anatomically distinct from those that generate vomiting. Further discussion of the pathophysiology is located in other topics. (See "Approach to the adult with nausea and vomiting", section on 'Pathophysiology' and "Prevention of chemotherapy-induced nausea and vomiting in adults".)

PATIENT ASSESSMENT — In many cases, the cause of the nausea and vomiting can be determined from the history and physical examination (table 1). Many patients have two or more contributing factors [1]. Additional laboratory investigations or imaging may be required depending on the clinical presentation and prognosis of the patient.

For patients near death, empiric treatment for nausea (eg, with haloperidol, metoclopramide, or chlorpromazine) is reasonable without a search for a specific etiology [2]. (See "Palliative care: The last hours and days of life", section on 'Nausea'.)

History and physical examination — Our approach to evaluation of nausea and vomiting includes taking a thorough history and physical examination. We use an approach similar to adults that are not in palliative care (see "Approach to the adult with nausea and vomiting", section on 'History and physical examination'). A list of the differential diagnosis of nausea and vomiting is in (table 2).

We also assess the following historical features in palliative care patients evaluating for the etiology of nausea and vomiting:

●Presence of vomiting and other symptoms – If patients have vomiting with nausea, we assess the timing, pattern, and whether vomiting gives relief from nausea as these can provide clues to the etiology. For instance, a proximal obstruction (gastric and small bowel) may be distinguished from a distal obstruction (distal small bowel and colon) by large-volume postprandial vomiting. By contrast, a distal obstruction is more likely to be accompanied by small-volume, malodorous (feculent) vomiting and abdominal distension [3]. Feculent vomiting can also be associated with a gastrocolic fistula. (See "Etiologies, clinical manifestations, and diagnosis of mechanical small bowel obstruction in adults" and "Acute colonic pseudo-obstruction (Ogilvie's syndrome)".)

In patients with gastroparesis or obstruction, nausea is usually relieved after vomiting; by contrast, patients suffering from drug, chemical, or metabolic causes have persistent nausea that is unrelieved by vomiting. Additionally, gastroparesis can be distinguished from mechanical obstruction by bowel movements and clinical response to prokinetic medications. (See "Gastroparesis: Etiology, clinical manifestations, and diagnosis" and "Gastric outlet obstruction in adults".)

Neurogenic vomiting may be positional as well as projectile and is usually associated with other neurologic signs or symptoms. (See "Overview of the clinical features and diagnosis of brain tumors in adults".)

●Medications and other treatments – We obtain a complete list of medications, both prescription and over-the-counter, as many medications including opioids, tramadol, nonsteroidal antiinflammatory drugs (NSAIDs), iron supplements, selective serotonin reuptake inhibitors (SSRIs), bupropion, antibiotics, and chemotherapy can contribute to nausea in palliative care patients (table 1). In patients with cancer, we determine the timing of prior treatments including chemotherapy and/or radiotherapy, and whether prophylaxis was given according to published guidelines.

Certain medications such as opioids (particularly in the first 72 hours after initiation of therapy), antibiotics, tramadol, NSAIDs, methylxanthines [4], and antidepressants should be considered as causes of nausea or vomiting (table 1).

●Pattern of bowel movements – We assess the consistency and the frequency of bowel movements and perform a digital rectal examination, if necessary, to assess the presence of a fecal impaction. Constipation is a frequent cause of nausea. The combination of autonomic dysfunction, opioids, use of serotonin 5-HT₃ antagonists as antiemetics, and a primary gastrointestinal tumor or metastases increases the risk for severe constipation that can exacerbate nausea.

●Symptoms of reflux – We ask about symptoms suggestive of gastroesophageal reflux disease (GERD). Heartburn with nausea often indicates. However, GERD can also present as chronic nausea without typical reflux symptoms [5]. (See "Clinical manifestations and diagnosis of gastroesophageal reflux in adults".)

On physical examination, we evaluate for the following signs:

●Abdominal signs and symptoms

•Abdominal distension and tenderness with high-pitched bowel sounds suggest malignant bowel obstruction (MBO). MBO should be suspected in a patient with progressively worsening colicky pain with diminishing stool and flatus. Among patients with advanced cancer, female sex [6] and tumor types such as gastrointestinal malignancies [7] and gynecologic malignancies are associated with increased risk of nausea and vomiting and also a greater risk of MBO.

•Patients who have hepatomegaly and/or ascites may have nausea and vomiting due to extrinsic compression on the stomach. For patients with malignant ascites, one prospective study of 24 patients demonstrated that placement of a permanent peritoneal port for periodic drainage improved nausea scores by two or more points on a 0 to 10 scale [8]. A larger prospective study of 48 patients also reported improvement of nausea and vomiting at one week after placement of a percutaneous tunneled drainage catheter, but improvement was not sustained at one month [9]. Vomiting of food eaten several hours earlier and a succussion splash detected on abdominal examination suggest gastric outlet obstruction or gastroparesis.

●Volume status – We assess the volume status of patients. Dehydration is thought to be associated with nausea in palliative care patients [10]. However, symptomatic improvement from parenteral hydration has not been shown in patients with advanced cancer. (See "Stopping nutrition and hydration at the end of life", section on 'Impact on target symptoms'.)

●Neurologic signs – Vertigo and nystagmus are typical of vestibular neuritis (labyrinthitis) and other causes of vestibular dysfunction. (See "Vestibular neuritis and labyrinthitis" and "Causes of vertigo".)

Patients who have accompanying personality changes or confusion associated with vomiting may also have metabolic abnormalities (eg, hyponatremia, hypercalcemia, adrenal insufficiency). Intracranial disease is more likely to present with headache and motor sensory deficits including hemiparesis and gait disturbance, whereas metabolic abnormalities are more likely to be associated with sedation or delirium. Delirium accompanied by nausea may also be due to sepsis.

Focal neurologic signs or papilledema would especially suggest raised intracranial pressure as an etiology for vomiting. (See "Overview and differential diagnosis of papilledema".)

Laboratory tests — Certain laboratory abnormalities may contribute to nausea and/or vomiting. These include:

●Hyponatremia – Nausea and vomiting can be signs of life-threatening cerebral edema in patients with acute hyponatremia. In contrast, in patients with chronic hyponatremia, nausea and vomiting is not life-threatening and seen in approximately one-third of patients. (See "Manifestations of hyponatremia and hypernatremia in adults", section on 'Clinical manifestations of acute hyponatremia' and "Manifestations of hyponatremia and hypernatremia in adults", section on 'Clinical manifestations of chronic hyponatremia'.)

●Adrenal insufficiency – Adrenal insufficiency may present with hyponatremia, hyperkalemia, and nausea and can be diagnosed if a serum cortisol level is <4 mcg/dL. This should be considered especially in patients who are receiving or may have received immunotherapy. (See "Clinical manifestations of adrenal insufficiency in adults", section on 'Chronic adrenal insufficiency'.)

●Elevated creatinine – As patients become more uremic with a decrease in kidney function, nausea and vomiting can occur. (See "Diagnostic approach to adult patients with subacute kidney injury in an outpatient setting", section on 'Clinical manifestations'.)

●Hypokalemia – A decrease in potassium levels can cause dysfunction in the gastrointestinal muscles, which results in an ileus causing nausea and vomiting. (See "Clinical manifestations and treatment of hypokalemia in adults", section on 'Manifestations of hypokalemia'.)

●Hypercalcemia – Hypercalcemia causes a variety of symptoms including a decrease in gastrointestinal motility and volume depletion, which can lead to nausea.

Imaging — Even in the palliative care setting, where the burden of diagnostic testing may outweigh the benefit, imaging may be appropriate if it identifies etiologies that, if addressed, may improve symptoms. As examples:

●In patients with nausea and no bowel movements, a plain abdominal radiograph can assist in the identification of constipation, ileus, or gastrointestinal tract obstruction. Abdominal computed tomography (CT) is more sensitive and specific than plain radiographs for diagnosing a bowel obstruction. However, the ability of CT to detect individual peritoneal implants is quite poor (<20 percent) when the tumor size is <1 cm [11].

●In patients with neurologic symptoms or signs, magnetic resonance imaging (MRI) of the brain might be useful if no recent imaging has been done. (See 'History and physical examination' above.)

MANAGEMENT

Approach — Our first step is to identify the etiology causing nausea and vomiting and, if possible, to direct treatment based on the underlying cause. (See 'Management according to etiology' below and 'Etiologies specific to patients with cancer' below.)

In patients without a clear etiology, we empirically treat with metoclopramide, a dopamine receptor antagonist. Other common classes of medications include histamine, serotonin 5-HT₃, and muscarinic (acetylcholine) receptor antagonists. (See 'Management with no obvious cause' below.)

Nonpharmacologic approaches — A variety of environmental and psychologic factors can contribute to nausea. Simple preventive measures such as minimizing the sights, sounds, and smells associated with nausea may be effective. Although avoidance of fatty, spicy, highly salted foods is frequently suggested [12], there are no published studies on the benefits of dietary modification in reducing nausea.

Acupuncture or acupressure may be of benefit for chemotherapy-induced nausea and vomiting (CINV) (see "Management of poorly controlled or breakthrough chemotherapy-induced nausea and vomiting in adults", section on 'Complementary therapies'). Available evidence is limited in other palliative care populations [13,14]; however, given the overall safety of this approach, interested patients may be referred for a trial of acupuncture if symptoms of moderate to severe nausea persist despite other forms of therapy.

Other complementary and integrative medicine measures (eg, ginger, guided imagery, progressive muscle relaxation, music therapy) have some evidence for benefit in control of nausea and vomiting; however, almost all studies have been conducted in patients with CINV [15], and their benefit in other palliative care populations is uncertain [16].

Management according to etiology — A summary of the approach to management of nonchemotherapy or radiotherapy-induced nausea and vomiting (RINV) in patients with terminal cancer is provided in the figure (algorithm 1). A detailed history and physical examination are required as they may provide clues to the etiology; investigations such as computed tomography (CT) scans or abdominal radiographs may also be required in selected patients. (See 'Patient assessment' above.)

Opioids — Opioids have three potentially emetogenic mechanisms: a direct effect on the chemoreceptor trigger zone, enhanced vestibular sensitivity, and delayed gastric emptying. Refractory constipation and stool impaction may be contributory. When present, constipation should be managed before addressing opioid-induced nausea. (See "Prevention and management of side effects in patients receiving opioids for chronic pain", section on 'Opioid bowel dysfunction'.)

Chronic nausea from opioid therapy usually responds to the same group of drug therapies that are used for acute nausea and vomiting; for example, the serotonin 5-HT₃ receptor antagonist ondansetron or the dopamine receptor antagonist prochlorperazine. However, the presence of other symptoms may change or influence the choice of anti-emetic. For instance, ondansetron may exacerbate constipation in patients who might already be experiencing opioid-induced gastrointestinal dysmotility. In addition, both metoclopramide and prochlorperazine can cause extrapyramidal symptoms, but metoclopramide has the advantage of causing less sedation and promoting gastric motility.

Opioid rotation or a change in route of administration could also be considered after trying anti-emetics, although the data to support benefit from any of these strategies are limited [17,18]. For patients who do not respond to opioid rotation, we initiate metoclopramide. If the symptoms do not improve on metoclopramide, we stop metoclopramide and switch to an atypical antipsychotic such as olanzapine or risperidone.

Adrenal insufficiency — The abrupt discontinuation of corticosteroids or megestrol acetate can precipitate nausea due to adrenal insufficiency for which cortisol treatment is indicated. (See "Causes of secondary and tertiary adrenal insufficiency in adults" and "Treatment of adrenal insufficiency in adults".)

Constipation — Severe constipation is another easily reversible cause of nausea. Some patients are able to improve bowel function by dietary modifications, including increased consumption of fluids and dietary fiber. Fiber should be discontinued, however, if the patient is debilitated, bowel obstruction is suspected, or hydration has been difficult to maintain. Patients who have passed no stool in several days and who have no evidence of bowel obstruction or ileus are likely to be impacted. It is often possible to clear the rectal vault and lower sigmoid colon with a mineral oil enema followed by an irritant enema, but manual disimpaction may be required. Once an impaction has been ruled out or cleared, laxative therapy may be started. (See "Management of chronic constipation in adults".)

There are numerous options for laxative therapy (table 3) and no data to suggest that any one approach is superior to any other. Refractory cases that do not respond to traditional laxatives, and where bowel obstruction has been excluded, may require the use of a peripherally acting mu-opioid antagonist such as methylnaltrexone. However, concerns have been raised about severe abdominal pain and bowel perforation in patients with advanced cancer who were receiving methylnaltrexone [19]. These concerns led the US Food and Drug Administration to issue a warning for clinicians to use caution in administering methylnaltrexone to patients with known or suspected lesions in the intestinal wall, and to stop the drug immediately for worsening of gastrointestinal symptoms [20]. (See "Prevention and management of side effects in patients receiving opioids for chronic pain", section on 'Management of refractory opioid-induced constipation'.)

Gastroduodenal dysmotility — Early satiety and vomiting of food eaten several hours earlier suggests gastroparesis. Dietary modification and pharmacologic management using prokinetics such as metoclopramide are discussed elsewhere. (See "Treatment of gastroparesis" and "Gastroparesis: Etiology, clinical manifestations, and diagnosis".)

Etiologies specific to patients with cancer

Chemotherapy — Chemotherapy is a well-known cause of nausea and vomiting. The single most important factor predicting the likelihood that nausea and/or vomiting will develop during chemotherapy is the intrinsic emetogenicity of the chemotherapy agent(s). Chemotherapy agents are divided into four emetogenic levels, which are defined by the expected frequency of vomiting in the absence of effective antiemetic prophylaxis (see "Pathophysiology and prediction of chemotherapy-induced nausea and vomiting", section on 'Chemotherapy agent'):

●High – >90 percent risk of vomiting

●Moderate – >30 to 90 percent risk of vomiting

●Low – 10 to 30 percent risk of vomiting

●Minimal – <10 percent risk of vomiting

The predicted emetogenicity of individual oral and parenteral chemotherapy agents is provided in (table 4 and table 5).

Three types of CINV are defined (acute, delayed, and anticipatory). Acute vomiting most commonly begins within one to two hours of chemotherapy and usually peaks in the first four to six hours. Delayed vomiting occurs more than 24 hours after chemotherapy. Anticipatory vomiting occurs prior to treatment as a conditioned response in patients who have developed significant nausea and vomiting during previous cycles of chemotherapy. (See "Pathophysiology and prediction of chemotherapy-induced nausea and vomiting", section on 'Types of emesis'.)

Management of each of these types is as follows:

●Acute and delayed vomiting – The medications used for CINV include serotonin 5-HT₃ antagonists, corticosteroids, and neurokinin-1 antagonists. Guidelines for prevention of CINV based upon emetic risk category are outlined in the table (table 6) and discussed in more detail elsewhere. (See "Prevention of chemotherapy-induced nausea and vomiting in adults".)

●Anticipatory vomiting – For patients with anticipatory nausea and vomiting (ANV), behavioral interventions such as guided imagery, biofeedback, and hypnosis have all shown benefit [21]. Benzodiazepines are the most useful pharmacologic therapy for ANV and have been combined with behavioral therapies or other antiemetics. This subject is discussed in detail elsewhere. (See "Prevention of chemotherapy-induced nausea and vomiting in adults", section on 'Anticipatory emesis'.)

●Management of breakthrough symptoms – The incidence of breakthrough symptoms despite prophylaxis is as high as 40 percent [22-26]. For patients with nausea and vomiting that occurs despite adequate antiemetic prophylaxis ("breakthrough" nausea and vomiting), it is important to make sure they are taking the correct dose and exclude other disease- and medication-related causes before considering changes to the antiemetic regimen. The majority of patients who have breakthrough vomiting have derived some benefit from the original antiemetic regimen employed, and additional agents can be added, such as olanzapine. If the patient was receiving chemotherapy with a low emetic risk and experiencing poor vomiting control, the antiemetic regimen could be adjusted to one typically used for a higher-risk group. The use of olanzapine for breakthrough CINV and a discussion of alternative agents, oral cannabinoids, acupuncture, and other complementary therapies is discussed separately. (See "Management of poorly controlled or breakthrough chemotherapy-induced nausea and vomiting in adults", section on 'Treatment'.)

Radiotherapy — Radiotherapy is an important cause of nausea in patients being treated for cancer.

●Risk stratification – The incidence and severity of radiotherapy-induced nausea and vomiting (RINV) are both treatment related (irradiated site and volume, single and total dose, fractionation schedule, techniques) and patient related. The most important factor appears to be the radiation field. Risk categories for vomiting based upon the site of irradiation stratify a patient's risk for RINV into four categories. Risk is between 90 and 100 percent for patients receiving total body irradiation; 30 to 90 percent for those receiving upper abdominal or craniospinal irradiation; 10 to 30 percent for those receiving brain, head and neck, thorax, or pelvic irradiation; and less than 10 percent for those receiving breast or extremities irradiation. This subject is discussed in detail elsewhere. (See "Radiotherapy-induced nausea and vomiting: Prophylaxis and treatment", section on 'Risk classification'.)

●Management – Specific guidelines for prophylaxis based upon these risk categories are available from the American Society of Clinical Oncology (ASCO) (table 7) [27] and largely follow published guidelines from the Multinational Association of Supportive Care in Cancer (MASCC)/European Society of Medical Oncology (ESMO) [28]. For patients being treated with concomitant radiotherapy and chemotherapy, antiemetic prophylaxis should be based upon the higher chemotherapy or radiotherapy vomiting risk category. Notably, in contrast to CINV, the evidence base from randomized trials to support these specific guidelines is more limited. (See "Radiotherapy-induced nausea and vomiting: Prophylaxis and treatment", section on 'Prevention and treatment' and "Prevention of chemotherapy-induced nausea and vomiting in adults", section on 'Estimating the risk of nausea and vomiting'.)

Few studies have examined the benefit of specific rescue strategies for treatment of breakthrough nausea in patient receiving prophylactic therapy for RINV. A serotonin 5-HT₃ receptor antagonist (eg, ondansetron) is an option. Alternatively, olanzapine is another reasonable option given its activity in delayed CINV. (See "Radiotherapy-induced nausea and vomiting: Prophylaxis and treatment", section on 'Rescue therapy' and "Prevention of chemotherapy-induced nausea and vomiting in adults", section on 'Olanzapine'.)

Raised intracranial pressure — Nausea and vomiting are present in up to 40 percent of patients with primary or secondary brain tumors [29]. Corticosteroids are first-line therapy for associated symptoms of nausea, given their ability to decrease intracerebral edema. Antiseizure medications such as carbamazepine may decrease nausea in a variety of conditions including leptomeningeal carcinomatosis [30]. (See "Management of vasogenic edema in patients with primary and metastatic brain tumors" and "Treatment of leptomeningeal disease from solid tumors", section on 'Hydrocephalus and increased intracranial pressure'.)

Gastrointestinal obstruction — Patients with cancer may develop upper or lower gastrointestinal tract obstruction due to intrinsic or extrinsic compression, adhesions, or postradiation fibrosis. Tumors can also impair bowel motility by infiltration of mesentery, nerves, celiac plexus, and bowel muscle. (See "Etiologies, clinical manifestations, and diagnosis of mechanical small bowel obstruction in adults".)

Gastroduodenal obstruction from either primary gastric or duodenal cancers or from extrinsically compressing tumors causes severe nausea and vomiting. Stenting usually provides adequate and sustained palliation. (See "Enteral stents for the palliation of malignant gastroduodenal obstruction".)

Malignant large and/or small bowel obstruction (malignant bowel obstruction [MBO]) is a well-recognized complication in patients with advanced intraabdominal or pelvic tumors. Most of these patients are inoperable, and their survival is generally short. Clinical management of MBO requires a specific and individualized approach that is based on disease prognosis and the objectives of care (algorithm 2). In most cases, there are few or no data addressing the relative value of palliative surgery versus medical management, and a decision to proceed to surgical intervention requires careful weighing of risks and benefits including an assessment of the estimated life expectancy and patient goals and preferences. This subject is discussed in detail elsewhere. (See "Palliative care of bowel obstruction in cancer patients".)

Other specific disease considerations — In patients with an advanced serious and/or life-threatening illness other than cancer, symptoms are most prevalent in patients with acquired immunodeficiency syndrome (AIDS) (43 to 49 percent), heart failure (17 to 48 percent), and chronic kidney disease (approximately 40 percent) [31,32].

Chronic kidney disease — Patients with chronic kidney disease are at increased risk of adverse events with many medications because of impaired renal excretion. Guidelines for drug prescribing in patients with kidney failure are available [33]. Treatment of nausea and vomiting in patients with advanced kidney disease is discussed separately. (See "Kidney palliative care: Conservative kidney management", section on 'Nausea and vomiting'.)

Motility disorders such as delayed emptying or gastroparesis may be associated with uremia, thereby leading to anorexia, nausea, and vomiting; this disorder is a frequent reason to initiate dialysis and usually resolves after renal replacement therapy has begun. Gastroparesis that is unresponsive to dialysis is sometimes caused by autonomic neuropathy, particularly as associated with diabetes. These patients usually respond to prokinetic drugs such as metoclopramide and erythromycin. (See "Unique aspects of gastrointestinal disease in patients on dialysis".)

HIV/AIDS — Prior to potent antiretroviral therapy (ART), nausea and vomiting in patients with (human immunodeficiency virus) HIV was largely due to opportunistic infections of the gastrointestinal tract or central nervous system. These opportunistic infections still need to be considered as an etiology, especially when T cell counts are <200. (See "AIDS-related cytomegalovirus gastrointestinal disease" and "Cyclospora infection" and "Toxoplasmosis in patients with HIV".)

A post-ART multicenter study found nausea and vomiting is still prevalent and ranged from 42 to 57 percent for nausea and 28 to 32 percent for vomiting. The proportion rating nausea and vomiting as "severe and distressing" ranged from 26 to 40 percent for nausea and 8 to 40 percent for vomiting, and there was a perception among patients that their symptoms were not adequately treated [34]. Nausea can be caused by most nucleoside reverse transcriptase inhibitors, nonnucleoside reverse transcriptase inhibitors, and protease inhibitors. The mechanisms of nausea as a result of these drugs can be varied, including mitochondrial toxicity, lactic acidosis, and pancreatitis. (See "Mitochondrial toxicity of HIV nucleoside reverse transcriptase inhibitors".)

No specific antiemetic can be recommended based upon evidence. In patients with advanced AIDS, there is limited evidence for the use of oral cannabinoids; however, they have a narrow therapeutic window and a risk for side effects [35].

Heart failure — A retrospective study showed that almost one-half of patients with heart failure complained of nausea during their last six months of life [36]; however, other symptoms such as anorexia, fatigue, and dyspnea [37] are more distressing. In this population, medications (eg, digoxin) are a particularly important cause of nausea and vomiting. For patients who do not have an identifiable cause for nausea, no evidence-based recommendations for a specific antiemetic can be made. However, the potential for prolongation of the corrected QT interval should be considered in drug selection. (See "Palliative care for advanced heart failure: Decision support and management of symptoms", section on 'Symptom management' and "Secondary pharmacologic therapy for heart failure with reduced ejection fraction", section on 'Digoxin'.)

Liver failure — Patients with end-stage liver disease have high symptom burden, with pain (65 percent) and nausea (58 percent) being most common [38]. Nausea may be due to various causes including gastroparesis or increased abdominal pressure or may be centrally mediated by circulating toxins and bilirubin. Treatment is discussed separately. (See "Palliative care for patients with end-stage liver disease", section on 'Symptom burden and management'.)

Management with no obvious cause

Metoclopramide — Metoclopramide is a reasonable initial choice for palliative care patients with nausea and vomiting for whom a cause is not identified [17], but we attempt to limit treatment to three months or less due to concerns regarding tardive dyskinesia (TD). The risks and benefits of continued use after three months should be carefully evaluated and discussed with patients.

Metoclopramide can be administered in several different formulations; however, the availability is limited for some of these. Our preference is to start the controlled-release formula, if available. Metoclopramide is more effective as a controlled-release formula and also may be more effective after eight days of therapy than on day 1 [39]. In patients with advanced cancer, controlled release metoclopramide is also well tolerated during short-term use, with no increase in frequency or severity of side effects compared with placebo [40]. Unfortunately, there is no controlled-release formula available in the United States.

If we are unable to start the controlled release formula, we start metoclopramide at 10 mg orally every four hours. Patients not responding to a divided dose of 40 to 60 mg/day may obtain relief with a continuous subcutaneous or IV infusion of up to 4 to 5 mg/hour (total = 100 to 120 mg/day) [41,42]. It is also available as a nasal spray, dosed as one spray (15 mg) in one nostril four times daily (30 minutes prior to each meal and at bedtime).

Supporting data for the use of metoclopramide are as follows:

●Metoclopramide alone – A systematic review of the treatment of nausea and/or vomiting in cancer patients unrelated to chemotherapy and radiation included 93 studies and 14 randomized trials; metoclopramide showed modest activity in reducing nausea compared with placebo [43]. However, the studies were limited by methodologic issues.

●Combining metoclopramide with other agents – Adding or combining antiemetics with different mechanisms of action (eg, serotonin 5-HT₃ receptor blockers, dopamine D₂ receptor antagonists such as chlorpromazine or haloperidol) has proven useful for preventing and treating CINV; however, the available evidence suggests that the addition of other agents to metoclopramide may not provide further benefit in controlling chronic nausea in patients with advanced cancer:

•A randomized controlled trial comparing the combination of dexamethasone and metoclopramide versus metoclopramide alone found no benefit for combination therapy [39].

•In another prospective study of patients with advanced cancer, the addition of a serotonin 5-HT₃ receptor antagonist to metoclopramide was more effective at controlling nausea after three days than was the combination of metoclopramide plus dexamethasone [44]. However, this study was limited by the relatively low dose of metoclopramide (only 10 mg three times/day); ideally, metoclopramide should be given every four hours because of its short half-life.

●Toxicities – Concerns about the risk of TD have decreased the use of metoclopramide [45]; however, a literature review suggests the risk of TD from metoclopramide use is likely to be <1 percent, much less than the estimated 1 to 10 percent risk previously proposed in national guidelines [46]. However, prolonged use for more than three months increases the risk of TD. Metoclopramide and other medications including haloperidol and olanzapine that cause drug-induced parkinsonism should be avoided in patients with Parkinson disease. (See "Palliative approach to Parkinson disease and parkinsonian disorders", section on 'Nausea'.)

Other options — Options other than metoclopramide exist for patients without a clear etiology of nausea.

•For terminally ill patients who have contraindications to or do not respond well to metoclopramide, a number of other centrally acting antiemetic agents (eg, haloperidol, chlorpromazine [or, where available levomepromazine], olanzapine) can be used. Extrapolating from studies in patients with gastrointestinal tract obstruction, haloperidol may be offered, recognizing that there are limited data in other palliative care settings [47-49]. There are no trials evaluating the use of chlorpromazine/levomepromazine; nevertheless, these recommendations are consistent with recommendations from MASCC [17].

A particularly well-tolerated option is olanzapine [50,51]. In a trial of 30 patients with advanced cancer and persistent nausea and vomiting lasting for at least one week, unrelated to chemotherapy or radiotherapy (baseline nausea severity 8 to 10 on a 10-point scale), olanzapine 5 mg daily for seven days was well tolerated and resulted in an 8-point greater reduction in nausea scores when compared with placebo [51]. Patients in the olanzapine arm also reported less vomiting, less use of other antiemetic drugs, better appetite, less sedation, less fatigue, and better wellbeing. Although larger trials are preferred to demonstrate benefit, olanzapine appears to be a reasonable alternative to metoclopramide in patients with advanced cancer and no clear etiology for the chronic nausea and vomiting.

•In the postoperative setting, serotonin 5-HT₃ receptor antagonists can be useful and may be considered in other clinical scenarios of refractory nausea. Tropisetron and levosulpiride are considered third-line antiemetics in patients with advanced cancer [17].

•Corticosteroids are commonly used in palliative care for a wide variety of nonspecific indications, including nausea. However, there are few studies assessing the effect of corticosteroids on nausea and vomiting not related to chemotherapy, radiotherapy, or surgery [39,44,52], and, at least in the setting of advanced cancer, there is very low-quality evidence from randomized trials that neither supports nor refutes the utility of corticosteroids in this setting [53]. The utility of corticosteroids in medical treatment of MBO is discussed elsewhere. (See "Palliative care of bowel obstruction in cancer patients", section on 'Pharmacologic management'.)

SPECIAL CONSIDERATIONS

Patients unable to take oral medications — For patients who are unable to take oral medications, metoclopramide, dexamethasone, and haloperidol can be safely administered intravenously and subcutaneously. Olanzapine may be given sublingually as an orally disintegrating tablet. Metoclopramide is also available in a nasal formulation. The rectal route can occasionally be used but may be uncomfortable for patients because of the need for frequent administration given the short duration of action of antiemetics. Inhaled isopropyl alcohol has been studied for relief of nausea but requires additional research before it can be recommended [54]. (See "Palliative care: The last hours and days of life", section on 'Nausea'.)

Avoidance of medical marijuana — We do not use medical marijuana for refractory nausea and vomiting in palliative care patients due to legal concerns and central nervous system side effects seen in older individuals. The use of medical marijuana is not included in the guidelines for (chemotherapy-induced nausea and vomiting) CINV from the National Comprehensive Cancer Network (NCCN), American Society of Clinical Oncology (ASCO), or Multinational Association of Supportive Care in Cancer (MASCC) [17,27,55]. Medical use of marijuana is legal in several countries (eg, the Netherlands and Canada) but despite legalization by several states, marijuana use is still illegal in the United States at the federal level [55]. (See "Medical use of cannabis and cannabinoids in adults".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Palliative care".)

SUMMARY AND RECOMMENDATIONS

●Etiology – Nausea and vomiting are common symptoms near the end of life. The etiology is often multifactorial. Common causes are outlined in the table (table 1). (See 'Pathophysiologic pathways' above.)

●Evaluation – In many cases, the cause of the nausea and vomiting can be determined from the history and physical examination. Additional laboratory investigations or imaging may be required depending on the clinical presentation and prognosis of the patient. (See 'Patient assessment' above.)

●General approach to management – We use an etiology-based rather than an empiric approach to selection of antiemetic agents. Dopamine, histamine, serotonin 5-HT₃ and 5-HT₄, and muscarinic (acetylcholine) receptor antagonists are all established classes of antiemetic and antinausea agents used in the palliative care setting. For life-limiting illnesses other than cancer, the assessment should be based on the approach to the adult with nausea and vomiting. (See "Approach to the adult with nausea and vomiting".)

●Etiologies specific to patients with cancer

•Chemotherapy – Guidelines for prevention of chemotherapy-induced nausea and vomiting (CINV) are based upon emetic risk category (table 6). Preventive treatment should be matched to the chemotherapy agent being used (table 4 and table 5). (See 'Chemotherapy' above and "Prevention of chemotherapy-induced nausea and vomiting in adults".)

•Radiotherapy – The risk for radiotherapy-induced nausea and vomiting (RINV) is stratified into four categories depending on radiation field (table 8). Specific recommendations for prophylaxis based upon these risk categories are available (table 7). (See "Radiotherapy-induced nausea and vomiting: Prophylaxis and treatment".)

●Other potentially treatable causes – Other specific management strategies may include treatment of medication-related side effects, correction of metabolic abnormalities, aggressive bowel care for constipated patients, opioid rotation in patients with suspected opioid-induced nausea and vomiting, use of prokinetic agents, and, in patients with cancer who have brain metastases, the administration of glucocorticoids followed by local therapy (radiation or surgery). (See 'Management according to etiology' above.)

●No obvious cause – If a potentially reversible cause cannot be identified and bowel obstruction is ruled out, we suggest symptomatic treatment with a prokinetic agent such as metoclopramide, rather than other medications or treatments (eg, nonpharmacologic methods, cannabis) (Grade 2C). Prolonged use of metoclopramide for more than three months increases the risk of tardive dyskinesia (TD). For patients who have contraindications to metoclopramide, a number of other centrally acting antiemetic agents (eg, haloperidol, chlorpromazine, olanzapine) can be used. Dopamine antagonists should be avoided in patients with Parkinsonian disorders. (See 'Management with no obvious cause' above and "Palliative approach to Parkinson disease and parkinsonian disorders".)

●Nonpharmacologic approaches – A variety of environmental and psychologic factors can contribute to nausea. Simple preventive measures such as minimizing the sights, sounds, and smells associated with nausea may be effective. Acupuncture or acupressure may be of benefit for CINV. (See 'Nonpharmacologic approaches' above.)

●Specific disease states – Considerations in specific disease states including end-stage kidney or liver failure, HIV, or heart failure are discussed above. (See 'Other specific disease considerations' above.)