Introduction

Nausea alone or nausea and vomiting (N&V) are common and often multicausal palliative care problems for persons with cancer. Estimated rates of N&V in advanced cancer vary highly, but incidence alone does not tell the entire story. Oncology professionals, particularly those in medical oncology, are well-versed in standard-of-care antiemetics for chemotherapy-induced N&V (CINV). However, there is scant research regarding palliative management of N&V. This article will address the mechanisms of nausea and of vomiting, the causes of N&V in advanced disease, the management principles, and the pharmacologic agents, incorporating palliative care principles of weighing benefits and burdens.

Box 1 Case—Mary F, 53 years old with recurrent ovarian carcinoma

Mary’s gynecological oncologist recently started her on carboplatin (4.5 AUC) plus paclitaxel (175 mg/m2) every 21 days for recurrent ovarian cancer. The hospital palliative care service (PCS) was consulted because of Mary’s persistent moderate to severe nausea. The PCS APN notes Mary appears overweight but not obese, mildly chronically ill, and may have (by appearance) ascites. She reports feeling “queasy” almost all of the time, and this worsens after chemotherapy. She is also troubled by abdominal fullness and early satiety after eating, and a little worsening of nausea when she moves her head. Her mood is even; she does not seem depressed or anxious. She denies pain, constipation, and other symptoms. Ondansetron plus DEX have been ordered for day 1 and for 3 days after chemotherapy. Mary’s treatment goal is palliative control, with a life expectancy of months to years.

Possible causes of nausea: acute and delayed CINV (suboptimal antiemetics), gastroparesis and early satiety (related to cancer and chemotherapy), mild abdominal compression (ascites), minor element of motion sickness, and anxiety related to inadequate control of CINV heightening risk.

Goals of Care, Prognosis, and Survival

Palliative care, symptom control, and quality of life (QOL) are paramount for patients at all points across the cancer continuum—from diagnosis and treatment to recurrence, progression, and end-of-life or to survivorship care [1]. Many people have curable cancer at diagnosis but most with recurrent or advanced disease do not. It is thus important to estimate each patient’s approximate survival: years, months to years, weeks to months, days to weeks, or hours to days—usually being a little optimistic. This aids in thinking about appropriate interventions and weigh benefits against acceptable burdens/harms. The steps in palliative care management of N&V are to 1) determine or confirm goals of care; 2) estimate a patient’s prognosis and duration of survival; 3) identify possible causes; 4) consider whether causes are reversible or require palliative interventions; and 5) select treatment options, considering potential benefits and burdens. Hawley’s [1] model of integrative palliative care (Fig. 1) can also be used for shared decision-making with the patient.

Fig. 1
figure 1

Bow tie model of integrated palliative care. a The Bow Tie Model (BPC) illustrates that palliative care is integrated across and throughout the disease continuum, including diagnosis and treatment, survivorship or hospice and end-of-life care. b The BPC can be used as a patient teaching tool to aid in discussing treatment goals and focus of care. Adapted from Journal of Pain and Symptom Management, Volume 47, Issue 1, “The Bow Tie Model of 21st Century Palliative Care,” pages e2–e5, ©2014, with permission from Elsevier.

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Nausea is a greater problem than vomiting in advanced cancer, and incidence increases with disease progression. A study that examined symptom severity and interference found patients rated nausea (after pain and fatigue) as most severe and most bothersome [2]. Even mild nausea (< 4/10) was bothersome, and patients with the most severe and most bothersome symptoms were highly depressed and anxious.

Mechanisms of Nausea and Vomiting

Nausea and vomiting are different physiologic processes initiated by the same events, having distinctive and overlapping mechanisms [3•, 4, 5••]. Activation of the same neural pathways has been assumed to induce nausea and vomiting, but newer information questions this notion. Vomiting, the forceful expulsion of gastric contents through the mouth, is a complex reflex mediated in the medullary brainstem nucleus tractus solitarius (NTS) and dorsal motor nuclei of the vagus (DMV)—the so-called central pattern generator or vomiting center (VC). Emesis occurs by coordinated efferent gastrointestinal (GI), diaphragmatic and abdominal muscle actions.

Nausea, an unpleasant and difficult to describe sensation in the stomach, is accompanied by a feeling of the need to vomit. Nausea has cognitive, emotional, and interoceptive domains, and forms in higher brain centers—the anterior insular cortex (AIC) and the anterior cingulate cortex (ACC), complementary regions activated together during subjective or emotional feelings. All internal sensations, including nausea, come together in the AIC. The ACC mediates cognitive and emotional influences, the amygdala adds negative value (stress, fear, and disgust), and other cortical regions also add input and influence [6, 7]. Nausea is more common, persistent, and difficult to control, more disabling and distressing than vomiting, and is associated with QOL symptoms (e.g., appetite loss) [8]. Physiologic stress response manifestations, including elevated plasma vasopressin, gastric dysrhythmia and decreased gastric emptying, and autonomic nervous system effects, often accompany nausea [5••, 9].

Causes of Nausea and Vomiting in Palliative Cancer Care

N&V in advanced cancer are often multifactorial and may have unclear etiologies. In a study of 821 adults with metastatic solid tumors, 375 (46%) had some degree of nausea; the most common identifiable causes were constipation (31.5%) and opioids (16.6%) [8]. “Other” causes (fungal infection or bacterial infections and reflux) accounted for 21.6%, but 42.3% had no identifiable cause. Opioid-induced N&V is not well understood, and antiemetics are often ineffective [10]. Other medications that may cause nausea include cardiovascular (e.g., digitalis [toxicity], antiarrhythmics, beta blockers and calcium channel antagonists), diuretics, hormones, GI (e.g., sulfasalazine, azathioprine), and central nervous system (CNS) (e.g., anticonvulsants) agents and theophylline [9].

Chronic nausea syndromes include impaired gastric emptying (35–45% of cases), characterized by intermittent nausea, early satiety and fullness or bloating after eating; nausea is relieved by small-volume emesis [11]. Chemically-caused nausea (30–40% of cases) is aggravated by the sight and smell of food and not relieved by vomiting. Early morning N&V with headache suggests raised intracranial pressure (ICP), nausea aggravated by movement points to a vestibular component, and N&V with anxiety suggests a cortical component; these account for > 15% cases. Bowel obstruction accounts for 10–30% cases (discussed later).

Assessing Nausea or Vomiting

Palliative management approaches to N&V, driven by assessment, are etiological or empirical [12, 13]. Diagnostic measures (and antiemetic selection) are tailored to suspected causes and focus on putative mechanisms, neurotransmitters and receptors involved. If a specific cause cannot be identified, the empirical approach dictates selecting a broad-spectrum, multipurpose antiemetic [9]. Assessment, outlined in Table 1, focuses on identifying causes of N&V and correcting reversible causes (e.g., suppository or enema to alleviate rectal impaction and scheduled laxatives to prevent constipation, switching to a different opioid when a first causes nausea, or discontinuing other drugs that cause nausea). Imaging procedures and other tests should be limited to those that confirm or rule out suspected causes and would likely impact treatment [14].

Table 1 Focused assessment for nausea and vomiting
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Malignant Bowel Obstruction

Malignant bowel obstructions (MBO) secondary to diffuse peritoneal disease, or from direct or indirect obstruction from malignant adhesions, is most common in patients with end-stage (life expectancy of weeks to months) colorectal or ovarian cancer [14]. MBO typically occurs and remits over several weeks; multiple levels of subacute obstruction upregulate peptides that inhibit gut motility and intensify mucosal edema, thereby increasing retained intraluminal secretions. All patients with complete MBO have nausea and most vomit, have abdominal distension, colicky pain, and have had no stools or flatus for ≥ 72 h [12, 14, 15•].

Patients with intractable vomiting or distressing gastric distention require nasogastric tube (NGT) placement with low, intermittent suction to decrease symptoms, prevent aspiration and rest the bowel, allowing an intermittent MBO to resolve. NGTs for longer than a few days may cause painful nostril ulcers, pharyngitis, or esophageal erosion [12, 14]. If NGT drainage > 1 l/24 h continues despite treatment, a venting percutaneous gastrostomy will alleviate N&V and may allow eating small amounts of soft or liquid foods for pleasure. Initial medical management includes intravenous (IV) fluids and electrolytes, a short course (< 10 days) of dexamethasone (DEX) or methylprednisolone to lessen inflammation and edema and add antiemetic effect, along with metoclopramide, haloperidol, olanzapine, or levomepromazine [12, 14, 15•]. Prokinetic-antiemetics (metoclopramide, mirtazapine or domperidone, and erythromycin) are contraindicated for suspected complete MBO because of increased risks for colicky pain and bowel perforation.

Octreotide, a synthetic somatostatin analog, is the first-line agent (with haloperidol or other antiemetic) for patients with complete MBO or peritoneal carcinomatosis, but high cost may dictate reserving it for when anticholinergic antisecretory drugs are ineffective for obstructive symptoms [12]. Octreotide blocks vasoactive intestinal polypeptide (VIP) release, reduces water, sodium, and chloride movement into the bowel, and increases water and electrolyte absorption from the bowel [16]. It more effectively and rapidly decreases vomiting episodes and nausea than anticholinergic antisecretory drugs [17, 18]. It is practical to start octreotide and escalate the dose as needed, and convert to lanreotide depo after 6 days if effective, or discontinue if not.

Anticholinergic antisecretory drugs (scopolamine, hyoscine-N-butyl bromide, or glycopyrrolate) have antispasmodic effects and reduce GI secretions [12, 14, 15•]. These agents—particularly glycopyrrolate—are generally well tolerated. Transdermal scopolamine is a convenient alternative to oral or parenteral administration.

Antiemetics Used in Palliative Care

In empirical management of N&V, a single antiemetic is started to assess its efficacy and adverse effects (AEs) [19]. If the drug decreases but does not totally alleviate N&V, the dose is increased as feasible. Antiemetics with no efficacy or that cause dose-limiting AEs should be discontinued and another started. Unlike antiemetics for CINV that target a single receptor, older drugs are “dirty” and bind to > 1 receptor (Table 2), allowing for a broader therapeutic effect but perhaps increasing AEs.

Table 2 Managing nausea or vomiting in palliative care
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The most recent Multinational Association for Supportive Care in Cancer (MASCC) guidelines reiterate that few, small studies support metoclopramide and haloperidol as first- and second-line antiemetics in advanced cancer [12, 20]. Prescribing patterns may be changing; in a recent report, olanzapine (followed by corticosteroids) is most commonly prescribed for patients with nausea [8].

Metoclopramide

Metoclopramide (titrated to effect) is still an antiemetic of choice in advanced cancer, with widely varying suggested oral (PO) and parenteral (intravenous, IV or subcutaneous, SC) doses [12, 20, 21]. Its antiemetic properties are related to antagonist effects at dopamine (D2) and serotonin3 (5HT3) receptors (at doses > 120 mg/day) [16, 21, 22]. Metoclopramide is also a 5HT4 agonist that accelerates gastric emptying and may alleviate gastroparesis [8]. Prokinetic actions explain its rationale for patients with partial MBO or ileus, and it is the same reason metoclopramide is contraindicated in patients with colic or complete MBO.

Extrapyramidal Syndromes

D2 antagonists are also responsible for acute extrapyramidal syndromes (EPS)—dystonias (~ 95% of metoclopramide-induced EPS’s) and akathisia and later occurring reactions. EPS occurs in only ~ 0.2% (1 in 500) of patients taking metoclopramide [8, 21], but the European Medicines Agency (EMA) (https://www.ema.europa.eu/en/news/european-medicines-agency-recommends-changes-use-metoclopramide) and the US Food and Drug Administration (FDA) both recommend limiting its use because of acute EPS and tardive dyskinesia—unless therapeutic benefit outweighs potential risks for particular patients. This is usually true for palliative care patients, particularly as most are at low risk and can be carefully monitored [8].

Dystonias (e.g., torticollis opisthotonus), uncontrollable contractions in ≥ 1 body muscle groups with prolonged body part twisting, may cause patients to feel a frightening sense of being unable to breathe [22, 23]. Dystonias occur after a D2 antagonist is started or a dose increase, happening shortly after administration to within a few hours or days and resolving within 24–48 h after stopping the offending drug [24]. Dystonias are most likely in children (6 times greater risk than adults) and young adults (under age 30), and are less common after age 45 [24, 25].

Akathisia secondary to metoclopramide or other D2 antagonists is often not recognized because it is infrequent and mimics other conditions (e.g., agitation, anxiety, restless leg syndrome, or movement disorder). Akathisia occurs in the lower extremities and is more common in older adult. Patients feel distressing tenseness or anxiety, restless, have the urge to move—like they cannot sit or stand still or have drawing sensations in their legs [24, 25]. They may persistently fidget, repetitively tap or shuffle their feet, shift their weight, rock, or pace. Akathisia may start within days after treatment and usually resolves after the drug is stopped. High doses and long treatment periods (months to years) increase the risk factors for later effects—tardive dyskinesia (involuntary repetitive, jerking movements in the face, neck, and tongue) and Parkinsonism, 1% and 4% of reactions respectively, are potentially irreversible.

The cornerstones of using medications that can cause EPS—especially acute reactions—are knowledge, patient/family teaching, consistent patient monitoring, and intervention/management. Physicians, nurses, and pharmacists must know that D2 antagonists (metoclopramide, haloperidol, and phenothiazines) can cause EPS, articulate the clinical manifestations of dystonias and akathisias, and identify first line management agents used for each (Table 3). A simple instruction sheet (1 or 2 syllable words that avoid medical jargon, short sentences, large font, brief content) can reinforce verbal teaching about EPS and include actions to take and who to call. Continued monitoring and communication between care providers and patient are essential to timely recognition and interventions [8, 23].

Table 3 Acute extrapyramidal syndromes
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Dystonic reactions are reversible with an IV antihistamine, benzodiazepine, or centrally acting anticholinergic agent administered over 2–3 min [21, 23]. Anticholinergic agents are less effective for akathisia than for acute dystonia or Parkinsonism. Low-dose (15 mg po) mirtazapine, a 5HT2A receptor antagonist, is the recommended first-line agent to alleviate akathisia, and a benzodiazepine may be added for anxiety [24,25,26]. Mirtazapine is as effective and better tolerated than propranolol (a beta-adrenergic blocker), limited by potential hypotension and bradycardia.

Haloperidol

Haloperidol is a butyrophenone and first generation (typical) antipsychotic agent used as an antiemetic in palliative care and is the first-line drug for delirium [16]. It has a long half-life (12–35 h) and can be given in a single dose at bedtime, which may enhance adherence [27, 28]. Antiemetic doses are PO 1.5–3 mg (or parenteral equivalent—half of PO doses) over 24 h; higher doses may not add further benefit. Haloperidol may control nausea in 65% of patients, and administering it with ondansetron may alleviate intractable N&V in advanced cancer [28, 29]. A recent prospective pharmacovigilance study of haloperidol for N&V was implemented in 22 multinational centers. One hundred fifty consecutive palliative care patients (86% with cancer) were started on haloperidol (median PO or IV dose 1.5 mg (0.5–5 mg)/24 h) [30]. At baseline, nausea was moderate (89%) or severe (11%) and 96.6% of patients had vomiting. Benefits were assessed at 48 h; N&V were completely controlled in 114 (79%). Harms were documented in 62 (26%) of patients on day 7, most commonly constipation, dry mouth, and sleepiness.

Haloperidol is a selective D2 receptor antagonist and can induce akathisia and tardive dyskinesia. Akathisia might incorrectly be assessed as terminal agitated delirium, and the dose mistakenly escalated instead of correctly stopping haloperidol and administering a 5HT2 antagonist [31]. Haloperidol has a black box warning for QTc interval prolongation and a risk for torsades de pointe (TdP). Table 4 lists other antiemetics (and many anticancer agents) that also have a confirmed or potential risk for prolonged QT and TdP [32, 33•]. However, most of these are only contraindicated in patients with congenital long QT syndrome, which is rare (1 in 2500 births) and characterized by an inherited germline potassium or sodium channel LQT gene mutation, prolonged basal QT interval, T wave abnormalities, syncopal episodes, and sudden cardiac death in otherwise healthy children and teenagers [34]. Routine electrocardiograms (EKGs) are not indicated in terminally ill patients and most non-cardiologist clinicians would not be able to appreciate millisecond (msec) QT changes [22].

Table 4 Medications used in oncology that may increase QTc and the risk for torsades de pointes
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Olanzapine

Olanzapine is useful for refractory nausea and for other symptoms (e.g., sleep, anxiety, and delirium); it has a long half-life (33 h, range 21–54 h) and can be given once daily (plus a second prn dose) [35]. An oral (PO) dissolvable form may obviate the need for parenteral administration. Olanzapine often increases appetite and causes weight gain, increases leptin, insulin, and blood lipids, and may cause asymptomatic transaminase elevations. It is a second-generation (atypical) antipsychotic with moderate to high affinity for multiple D, 5HT, alpha adrenergic (α), histamine (H), and muscarinic cholinergic (M) receptors [22, 35, 36]. EPS is much less common than with haloperidol [31].

In a personal conversation, Dr. Rudy Navari stated psychiatrists’ observations that olanzapine decreased nausea led to numerous successful prospective trials of olanzapine for CINV (R Navari 2019, personal communication, 22 June). Olanzapine is the recommended second-line agent for palliative patients with N&V uncontrolled by standard antiemetics. A prospective pilot study suggested a dose-response: cancer patients’ nausea decreased significantly as placebo was changed to olanzapine 2.5 mg and escalated to 5 mg and then 10 mg [37]. Five and 10 mg doses were significantly superior to 2.5 mg, but patients rated QOL as highest with 5 mg, perhaps because of AEs. After other antiemetics (haloperidol, ondansetron, metoclopramide, and promethazine) were ineffective, MacKintosh [31] successfully managed a patient’s N&V with olanzapine; he subsequently accrued a prospective case series of 14 cancer patients whose N&V were similarly controlled with olanzapine 5 mg at bedtime (HS). In another retrospective study, olanzapine (2.5 to 20 mg/day) significantly reduced nausea in 90% and vomiting frequency in 80% of cancer patients with MBO [38]. Olanzapine oral dissolvable tablets (ODT) are suitable for patients with dysphagia or MBO and may obviate the need for SC or IV administration [16].

Mirtazapine

Mirtazapine, a tetracyclic antidepressant, may increase appetite, lead to significant weight gain, and lessen several other symptoms [39, 40]. Allen and others [40] completed a retrospective chart review of medically ill inpatients (most without psychiatric diagnoses) for whom psychiatric liaison practitioners had recommended mirtazapine for specific physical symptoms. Over 4.5 years, 475 were started mirtazapine for sleep, nausea, pain, or appetite; improvement was noted for about 38%, 37%, 36%, and 24% of patients, respectively. Mirtazapine was generally well tolerated; the most common AEs were daytime sedation (5.3%), worsening mental status (2.3%), and nightmares (1%).

Mirtazapine has complex pharmacology and high affinity for numerous D, 5HT, α adrenergic, H, and M receptors [41]. It also has prokinetic properties. Healthy adults with symptomatic gastroparesis started on 15 mg PO at HS reported significantly improved nausea, vomiting, retching, and appetite loss [42]. The effects mirtazapine on gastric emptying was also studied in 28 cancer patients with anorexia [43]. At baseline, 7 (25%) had normal gastric emptying, whereas after 15 days of mirtazapine (7.5 mg once daily), this was significantly improved in 64% and 52% had normalized gastric emptying. It is well tolerated that side effects are generally mild and may diminish, even with dose increases. Mirtazapine has a long half-life (21 h, range 20–40 h) and usually require once daily dosing [35].

Corticosteroids

Corticosteroids, thought to act via several unidentified mechanisms and pathways, may be effective for N&V from multiple or undetermined causes, particularly when administered with other antiemetics. They have broad-spectrum antiemetic activity for N&V from central nervous system (CNS) or GI causes, including primary or metastatic brain tumors, raised intracranial pressure (ICP) from other causes, MBO, or chronic nausea of advanced cancer [11, 12, 19]. Pharmacokinetic differences contribute to variable efficacy and AEs. DEX, most commonly prescribed, has a long half-life (≤ 36 h) and can be administered once daily, while duration of action for prednisone, prednisolone, and methylprednisolone are 12 to 36 h [19]. Large daily doses and longer treatment courses lead to a greater likelihood of AEs. Thus, the lowest possible corticosteroid dose should be used for the shortest time, the dose titrated down once maximal effect is reached, after an adequate trial (7–10 days) without desired effect or if dose-limiting AEs occur [11, 44].

In a recent systematic review of corticosteroids for N&V in advanced cancer, only 3 studies met inclusion criteria; these compared PO DEX with placebo, chlorpromazine, metoclopramide, or tropisetron [45]. The authors concluded evidence is insufficient to support or refute corticosteroid antiemetic efficacy in palliative care. Another such review included 27 randomized controlled trials (RCTs) and 12 observational cohort studies that examined AEs of corticosteroid prescribed for any reason to patients with advanced cancer; N&V was the primary outcome in 8 RCTs [46]. Almost 60% of studies did not report a method for assessing AEs, which could underestimate actual corticosteroid harms, and only 3 cohort studies used a validated AE assessment tool.

Phenothiazines

Phenothiazines are infrequently used to manage N&V in palliative care, but may be appropriate for patients unresponsive to first or second line antiemetics [11, 12, 47]. They act at several receptors and have broad actions, and may be useful for patients with MBO. They are D2 receptor antagonists and can cause EPS.

Levomepromazine (methotrimeprazine in the US), an antagonist several D, H, M, α-adrenergic, and 5HT receptors, is used to treat N&V and severe end-of-life delirium or agitation in non-ambulatory patients. It also has analgesic properties (for moderate to severe pain) and may be more cost-effective than other antiemetics [11, 47]. Levomepromazine’s half-life is 15–30 h, which may allow once daily dosing. It is more sedating and more likely to cause postural hypotension than chlorpromazine, while dystonia, Parkinsonism, and neuroleptic malignant syndrome are uncommon. It should be used cautiously (or avoided) in ambulatory patients, particularly those with renal or hepatic impairment.

Domperidone is an unusual phenothiazine; it is a potent peripheral D2 antagonist, but does not penetrate into brain structures in rats [48]. Others posit it antagonizes D binding in the chemoreceptor trigger zone (CTZ), which is not enclosed in the blood–brain barrier (BBB), and further blocks transmission of neural impulses to the vomiting center [49, 50]. Domperidone also binds with GI cholinergic D2 receptors to mediate smooth muscle effects, thereby significantly improving gastric dysmotility and delayed emptying. There are few case reports of domperidone-induced EPS in adults (and children) administered parenteral or high PO doses, and the risk is minimal with doses ≤ 30 mg/day.

Domperidone data are conflicting, but case reports and case-control studies have raised concerns about prolonged QT and ventricular arrhythmias [51]. A meta-analysis of 9 retrospective studies with 101,155 patients examined cardiac (CV) risks of domperidone and metoclopramide; risk was lower with domperidone than metoclopramide, but a greater than no treatment [50]. Subgroup analysis of doses found no CV event risk with domperidone ≤ 30 mg/day, but risk increased with larger doses. Another retrospective chart review of patients with N&V who received domperidone 80 to 120 mg doses concluded these doses were efficacious and had minimal risk for CV AEs [52]. One prospective study examined the cardiac safety of domperidone (30 and 80 mg per day) in 246 patients followed for > 1–4 years (mean 1.67 years) [51]. QTc interval was evaluated on EKGs at baseline (N = 246), at 2 to 6 months (N = 170), 6 to 12 months (N = 135), and ≥ 12 months (N = 152) after starting domperidone. The primary and secondary study endpoints were clinically significant prolonged QTc (> 500 msec) and clinically non-significant QTc prolongation. No patients experienced a QTc of > 500 msec, but 15 (6.1%) had non-clinically significant prolonged QTc. The authors concluded doses of 30–80 mg/day are safe and intensive EKG monitoring of all patients is unnecessary.

Chlorpromazine, effective in 20–30% of patients, and prochlorperazine are not commonly used antiemetics for patients with advanced cancer [11, 21]. Both are available as rectal suppositories, a potentially useful short-term option for patients at home with worsening N&V. Chlorpromazine is more sedating than prochlorperazine, but this might be beneficial in actively dying patients. Chlorpromazine can cause severe tissue necrosis and SC is contraindicated, and prochlorperazine should not be given to patients with an absolute neutrophil count of 1000 cells/μl because of increased risk for neutropenia. Confusion, EPS, and anticholinergic effects may be minimized by gradual dose titration.

Cannabinoids

In the 1970’s, anecdotal reports of decreased post-chemotherapy nausea in patients who smoked marijuana led to studies investigating dronabinol and nabilone for CINV (and appetite in AIDS patients). A relatively small number of controlled trials led to approval of both for CINV not controlled with standard antiemetics. However, interest in cannabinoids languished with development of 5HT3 antagonists. The research base for synthetic cannabinoids (dronabinol and nabilone) and of phytocannabinoids (tetrahydrocannabinol [THC] and cannabidiol [CBD] for palliative management of N&V is limited to few case reports or case series [53,54,55]. Patients typically had visceral metastases or abdominal carcinomatous with ascites and had received several other antiemetics (e.g., prochlorperazine, DEX, metoclopramide, haloperidol, ondansetron) without effect before starting dronabinol. Resolution of both N&V were reported as rapid and dramatic and sometimes accompanied by improved appetite and oral intake, decreased pain, and improved social interactions.

Two events are changing the landscape of general disinterest in cannabinoids: the discovery of the endocannabinoid system around 1990 and its roles in virtually every body system and changing sociocultural attitudes about therapeutic cannabis (medical marijuana) with loosening legal restriction in many countries [56, 57, 58••]. Israel’s government-mandated medical cannabis program began in 2007, and investigators collected routine treatment data for 2970 cancer patients prescribed medical cannabis and followed for > 2 years [59•]. Data were analyzed to identify symptoms, efficacy and safety of cannabis. At baseline, patients had an average of 11.1 ± 7.5 symptoms (e.g., sleep problems, severe pain, weakness, and lack of appetite) related to advanced solid tumors; 65% reported nausea. After six months, ~ 96% reported improvement, which was greatest for nausea (91%), followed by sleep, restlessness, anxiety and depression, pruritus, and headaches (> 80% improvement). Less than 20% reported “good” QOL at baseline, while ~ 70% did so after 6 months on medical cannabis. Fewer than a third reported ≥ 1 minor (and easy to cope with) side effects.

Similarly, Abrams [60], an oncologist in California where medical marijuana has long been available, recognizing the weakness of cannabis clinical trial data wrote “…I need a clinical trial to demonstrate that cannabis is an effective antiemetic about as much as I need a placebo-controlled trial to demonstrate that penicillin is an antibiotic!” (PS10). He quoted one (of many) patients who finally used cannabis near the end of his chemotherapy, “…did not use it until my last 5 sessions of chemo (me getting over the stigma of its use), it did what no other drug could do, completely solved the severe nausea I had...allowed me to play with my children…function very normally in day to day activities. I cannot thank you enough for giving me that option!”.

Conclusions

Nausea or N&V in patients with advanced cancer are complex problems that may present a greater treatment challenge than cancer pain. A patient’s primary oncology team can usually manage N&V in almost all instances. For patients who have the most complex, difficult to manage symptoms, palliative care specialists may add expertise. Such collaborative efforts among physicians, nurses, and pharmacists are most likely to maximized patient symptom control and QOL.

Box 2 Case continued—Mary F

Aprepitant was added to Mary’s palliative chemotherapy antiemetic regimen (per guideline recommendation). Her nausea improved, but was not totally relieved. PO mirtazapine (7.5 mg at HS) was added. Within 3 days, her nausea was 0–1 (0 to 10 scale), although she still had “a little nausea” with movement, and her appetite was improved. Mary, with her oncology and palliative care team, decides not to add further medications (that might add side effects) at this time.

Mary’s N&V was well controlled over many months during which she continued carboplatin/paclitaxel, and when she was started on a salvage regimen after disease progression. Soon after, she experienced worsening N&V, increased anorexia, post-prandial fullness, and ascites. Mirtazapine was increased to 15 mg at HS, which increased sleepiness. She wanted to try this for a few days to see if her nausea and sleepiness improved (they did). The PCS again saw Mary when she experienced rapid disease progression with declining performance status, massive ascites, and symptoms of MBO. Her oncologist explained further chemotherapy would add only toxicity without any benefit; she and Mary decided to focus solely on aggressive palliative care. Mary had a venting gastrostomy and a tunneled peritoneal catheter (for as needed drainage of ascites) placed so she could be cared for at home. Mirtazapine was switched to olanzapine ODT (5 mg at HS and 5 mg Q 4–6 h PRN). Mary was able to stay at home with PCS support. She died peacefully, surrounded by family, weeks later.