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CLINICIAN’S CORNER
Management of Intractable Nausea
and Vomiting in Patients at the End of Life
“I Was Feeling Nauseous All of
the Time . . . Nothing Was Working”
Nausea and vomiting, symptoms that occur commonly near
the end of life, represent a substantial source of physical
and psychological distress for patients and families. In the
context of the case of Mr Q, a 50-year-old man with meta-
static esophageal cancer admitted to the hospital with in-
THE PATIENT’S STORY
tractable nausea and vomiting, we review the evaluation
Mr Q is a 50-year-old electronics designer with metastatic and treatment of this symptom complex. A thorough his-
esophageal cancer treated with third-line palliative chemo- tory and physical examination are essential first steps in
therapy. Recently, he has spent more than half of his time inbed due to a general lack of energy, although he walks with- the management of these patients because they define the
out assistance or dyspnea. He was admitted to a university severity of the symptoms and clues to their underlying
hospital in May 2006 for intractable nausea and vomiting.
etiology. Once the most likely cause is determined, the
His medical history was remarkable for migraine head- clinician discerns the mechanism, specific transmitters, and
aches, depression, and ulcerative colitis during childhood.
receptors by which this etiology is triggering nausea
He was diagnosed with esophageal cancer by endoscopic bi- and vomiting. Subsequent pharmacological management
opsy in October 2005. Thoracic computed tomography (CT) focuses on prescribing the appropriate antagonist to the
scans at the time showed circumferential thickening of thedistal esophagus and an enlarged gastrohepatic lymph node.
implicated receptors. If symptoms are refractory despite
In December 2005, he began presurgical chemotherapy with adequate dosage and around-the-clock prophylactic ad-
docetaxel and capecitabine. In February 2006, he under- ministration, an empirical trial combining several thera-
went an exploratory laparotomy but the tumor was found pies to block multiple emetic pathways should be attempted.
to be unresectable. A 20 ϫ 20-mm stent was inserted in the Less traditional agents are also discussed, although evi-
gastroesophageal junction for impending obstruction and dence for their use is limited. Often, oral administration
a jejunostomy feeding tube ( J-tube) was placed. In March of medication is not feasible and alternate routes such as
2006, CT scans showed evidence of liver metastases.
rectal suppositories, subcutaneous infusions, and orally
Mr Q had experienced intermittent nausea and vomiting throughout his course of chemotherapy and reported a pain- dissolvable tablets should be considered. Using this step-
ful burning sensation in the chest and epigastrium since the wise approach, nausea and vomiting can be successfully
esophageal stenting. Ten days before admission he had be- managed in most patients at the end of life.
gun palliative chemotherapy with capecitabine. After- wards, his nausea and vomiting worsened considerably, withvomiting episodes occurring up to 10 times a day, consist- Author Affiliations are listed at the end of this article.
ing of both dry heaves and emesis of bilious fluid. There was Corresponding Author: Gordon J. Wood, MD, Section of Palliative Care and Medi-
no apparent temporal relation of these symptoms to oral in- cal Ethics, Institute to Enhance Palliative Care, University of Pittsburgh School of Medi-
cine, 200 Lothrop St, Suite 933 W, Pittsburgh, PA 15213 ([email protected]).
Perspectives on Care at the Close of Life is produced and edited at the University
of California, San Francisco, by Stephen J. McPhee, MD, Michael W. Rabow, MD,
and Steven Z. Pantilat, MD; Amy J. Markowitz, JD, is managing editor.
CME available online at www.jama.com
Perspectives on Care at the Close of Life Section Editor: Margaret A. Winker, MD,
Deputy Editor.
1196 JAMA, September 12, 2007—Vol 298, No. 10 (Reprinted)
2007 American Medical Association. All rights reserved.
MANAGEMENT OF INTRACTABLE NAUSEA AND VOMITING take or J-tube feedings. Normal daily bowel movements were Using the case of Mr Q, this article reviews a general ap- noted and a trial of ondansetron was not effective. He and proach to caring for patients with nausea and vomiting near his wife became worried about his inability to keep down the end of life, relying on empirical evidence, and in its ab- food or water so they came to the emergency department.
sence, our clinical experience. The approach involves: (1) On admission to the hospital, Mr Q received intravenous careful evaluation to determine the etiology of the present- fluids and nothing by mouth; however, his nausea and vom- ing symptoms; (2) using pathophysiology to determine the iting persisted. At that time, his antiemetic regimen con- mechanism and, subsequently, receptors underlying the pa- sisted of 8 mg of ondansetron intravenously twice a day; a tient’s nausea and vomiting; and (3) choosing an anti- scopolamine patch, 1.5 mg topically; lorazepam, 1 mg intra- emetic to block the implicated receptors. Because of its im- venously every 4 to 6 hours as needed; and promethazine, portance at the end of life, this article places a special 12.5 to 25 mg intravenously every 4 to 6 hours as needed.
emphasis on how to approach intractable nausea, defined Additional medications included oral morphine elixir as herein as nausea and vomiting that is not adequately con- needed, bupropion, docusate, potassium chloride, and trans- trolled after multiple antiemetics are used in series and/or dermal and transmucosal fentanyl. Upon physical examina- in combination. Although we believe a mechanism-based tion, his mucus membranes were moist, with no oral thrush.
approach is applicable to any patient with nausea and vom- His abdominal examination revealed no tenderness or dis- iting, this article’s focus may not be generalizable to popu- tention, no hepatosplenomegaly, and normoactive bowel lations with less limited life expectancies.
sounds. Laboratory studies were unremarkable including anormal complete blood count, electrolyte panel, liver func- EVALUATION
tion tests, amylase, lipase, and urinalysis. An abdominal and A history and physical examination represent essential first pelvic CT scan showed no abnormally dilated bowel loops.
steps in the evaluation of nausea and vomiting, for they pro- A palliative care consultant, Dr O, was asked to assist with vide a measure of symptom severity8 and clues to the un- management of the patient’s nausea and vomiting.
derlying etiology. Careful evaluation permitted physiciansin one study to confidently establish the cause of nausea and PERSPECTIVES
vomiting for about 45 (75%) of 61 hospice patients.9 The A Perspectives editor interviewed Mr Q and Dr O in May most frequently cited etiologies were chemical abnormali- ties (metabolic, drugs, infection; 33%), impaired gastric emp- MR Q: I was just feeling terrible. . . . I was nauseous all of tying (44%), and visceral and serosal causes (bowel ob- the time and throwing up. My energy level was really low, and struction, gastric bleed, enteritis, constipation; 31%).9 A study I was dropping weight. What prompted me to go into the hos- of 40 patient-episodes of nausea, vomiting, or both on a pal- pital was . . . I really just couldn’t eat or drink anything. Even liative care unit identified 59 reversible etiologies, with medi- feeding through a J-tube . . . was making me nauseous. My wife cations (51%) and constipation (19%) presenting most and I were afraid that I was starving. . . . [W]e went to the emer- gency department and did the long wait there. . . . They couldn’t The history should focus on characterizing the nausea and tell me to go home without figuring out how to give me food vomiting as well as any associated symptoms (TABLE 1).11,12
Special attention should be paid to complaints of anorexia be- DR O [PALLIATIVE CARE PHYSICIAN]: We were called to con- cause it may represent a constant low-grade nausea. Al- sult on [Mr Q] by the primary medical team for symptom though Mr Q did not have a history of constipation, given its management. . . . He [was] not eating much and feeling weaker frequency near the end of life,10 constipation must be ruled out in every patient.11,13 This includes a detailed history of the Nausea and vomiting are common symptoms at the end frequency and consistency of stools because many patients with of life, occurring in 62% of terminally ill cancer patients with limited oral intake mistakenly believe it is normal to have in- a prevalence of at least 40% during the last 6 weeks of life.1 frequent bowel movements. Mr Q reported esophageal burn- Although most extensively studied in the cancer setting, nau- ing consistent with gastroesophageal reflux, a common com- sea and vomiting also occur frequently in other terminal ill- plication after esophageal stent placement.14 nesses such as congestive heart failure and AIDS.2,3 In a ret- Obtaining a complete medication history is essential, in- rospective review of 100 consecutive patients with varying cluding a thorough evaluation of new and recently discon- diagnoses admitted to a palliative care unit, 71% reported tinued prescription and over-the-counter drugs. Chemo- nausea during their stay.4 Nausea often presents with a clus- therapeutics, opioids, antidepressants, and antibiotics are ter of symptoms5; in one study, 25% of cancer patients treated frequent contributors to nausea and vomiting near the end for pain also reported nausea.6 Nausea and vomiting cause of life.15 Recent and/or rapid discontinuation of corticoste- substantial psychological distress for patients and families roids or high-dose progesterones may cause nausea due to near the end of life,7 with poorly controlled symptoms con- tributing to fears about starvation, dehydration, and even Nonpharmacological therapies must also be considered in the evaluation. Radiation therapy, especially to the ab- 2007 American Medical Association. All rights reserved.
(Reprinted) JAMA, September 12, 2007—Vol 298, No. 10 1197
MANAGEMENT OF INTRACTABLE NAUSEA AND VOMITING domen or lumbosacral spine, can trigger nausea and vom- meningeal tumor can be emetogenic as well.12 Finally, a patient’s iting.17 Any recent surgery, particularly abdominal sur- psychological state, particularly anxiety or depression, may gery, can also produce symptoms.18 In the case of Mr Q, the be associated with nausea.20 Mr Q’s past medical history of mi- esophageal stent placement, palliative capecitabine (though graines and ulcerative colitis can cause nausea but currently a low emetic risk agent), and opioid therapy could all be appear quiescent. Esophageal cancer, through direct exten- contributing to his nausea. Bupropion and potassium chlo- sion, may irritate the esophageal or gastric mucosa, causing ride can be emetogenic, but represent long-standing thera- nausea and vomiting. Mr Q does not appear to have any dis- pies for Mr Q and, as such, are less likely causes of his The physical examination provides additional clues to the The past medical history provides additional critical clues.
etiology of a patient’s nausea and vomiting with important Peptic ulcer disease, gastroesophageal reflux, or both may ex- findings listed in Table 1. Mr Q, however, presented with a plain symptoms. Diabetes mellitus, alcoholism, chronic re- normal abdominal, rectal, and neurological examination.
nal failure, advanced cancer, autoimmune disorders, amyloi- Laboratory and radiology testing may provide diagnos- dosis, and Parkinson disease are all associated with autonomic tic insights, but for patients in the home setting an exhaus- dysfunction and delayed gastric emptying.19 For cancer pa- tive workup often distracts from minimizing symptom bur- tients, the type of malignancy, its site of origin, and location den and optimizing management.11 A laboratory evaluation of metastases are dispositive. For example, liver metastases, may reveal renal failure, hyponatremia, liver failure, pan- malignant bowel obstruction, and peritoneal carcinomatosis creatitis, or hypercalcemia, all of which may cause or con- can all cause nausea and vomiting.12 External compression of tribute to nausea and vomiting. Drug toxicity from digoxin the stomach or duodenum by tumor or massive ascites is as- or anticonvulsants can precipitate symptoms and, if sus- sociated with nausea and vomiting through the “squashed- pected, may warrant checking a serum level. A supine ab- stomach syndrome.”12 Primary or metastatic brain or lepto- dominal film helps identify constipation,13 and is espe- Table 1. History and Physical Examination: Clues to Specific Etiologies of Nausea and Vomitinga
Element of History or Physical Examination
Suggested Etiology of Nausea and Vomiting
Large, infrequent vomitus that relieves nausea Vertigo and symptom association with movement Morning symptoms with morning headache and neurological symptoms Uremia, hyponatremia, or increased intracranial pressure Decreased frequency of bowel movements, abdominal fullness, hard Esophageal burning, sour taste in mouth, worse with lying down Orthostatic blood pressure and pulse changes or absence of heart rate Abdominal distention and abnormal bowel sounds Bowel obstruction, ileus, or constipation a See text for comorbidities and therapies that may directly contribute to nausea.
1198 JAMA, September 12, 2007—Vol 298, No. 10 (Reprinted)
2007 American Medical Association. All rights reserved.
MANAGEMENT OF INTRACTABLE NAUSEA AND VOMITING cially useful in patients with delirium or dementia who are 1. Chemoreceptor trigger zone (CTZ): functionally out- unable to give an accurate history of recent bowel move- side the blood-brain barrier, the CTZ is exposed to toxins ments. Finally, an upright abdominal film can identify air- in the bloodstream and cerebrospinal fluid that can stimu- fluid levels if gastrointestinal (GI) tract obstruction is sus- pected. Mr Q’s laboratory studies were unremarkable, and 2. Cortex: thought to cause nausea due to input from the a CT scan did not show evidence of bowel obstruction.
5 senses, anxiety, meningeal irritation, and increased intra-cranial pressure, the cortex supplies many afferents to the MECHANISM
The 4 Pathways
3. Peripheral pathways: the main emetogenic input from DR O: I went down a lengthy list of the . . . causes of intrac- the periphery, these are triggered by mechanoreceptors and table nausea and vomiting. . . . It’s important to have an etio- chemoreceptors in the GI tract, serosa, and viscera and trans- logic diagnosis, so you know which treatments are going to be mitted via the vagus and splanchnic nerves, sympathetic gan- After elucidating the most likely etiology of nausea and vom- 4. Vestibular system: mediated through labyrinthine in- iting, the next step is to determine which mechanism is trig- puts into the vomiting center via the vestibulocochlear nerve, gering symptoms to guide therapy. Nausea and vomiting are nausea and vomiting are triggered by motion.
caused by the stimulation of at least 1 of the 4 pathways. Each Pathophysiology of Common Etiologies
of these provides input into the vomiting center in the brain-stem, which produce nausea or vomiting when the mini- Opioid-Induced Nausea and Vomiting. Up to 40% of opioid-
mum thresholds are reached (FIGURE). The 4 pathways
treated patients experience nausea and vomiting,25 trig- gered by constipation, stimulation of the CTZ, gastropare- Figure. Interrelationships Between Neural Pathways That Mediate Nausea and Vomiting
glossopharyngeal nerves,sympathetic ganglia Achm indicates muscarinic acetylcholine receptor; D2, dopamine type 2 receptor; GERD, gastroesophageal reflux; GI, gastrointestinal; H1, histamine type 1 receptor;NK1, neurokinin type 1 receptor; 5HT2, 5-hydroxytryptamine type 2 receptor; and 5HT3, 5-hydroxytryptamine type 3 receptor.
2007 American Medical Association. All rights reserved.
(Reprinted) JAMA, September 12, 2007—Vol 298, No. 10 1199
MANAGEMENT OF INTRACTABLE NAUSEA AND VOMITING sis, and sensitization of the labyrinth.26 The effects in the MR Q: They started me on different [combinations of] pain CTZ are largely mediated through central dopamine type 2 and antinausea medications. The thing that made the most dif- (D2) receptors, whereas the gastroparesis is mediated through ference, I think, is when they put me on an antacid called peripheral D2 receptors. Although early studies attributed [lansoprazole]. . . . [t]he acid reflux got better 2 or 3 days later. opioid-induced nausea and vomiting to the accumulation It was in conjunction with other anti-nausea medications. . . . By of metabolites, particularly morphine-6 glucuronide,27 more the second day, I wasn’t taking in anything orally, but I wasn’t recent studies do not support this theory.28 Chemotherapy-Induced Nausea and Vomiting. Chemo-
Thoughtful evaluation to determine both the etiology of therapy causes nausea and vomiting by a complex set of the symptoms and the pathophysiological mechanism by mechanisms.29 First, chemotherapy is thought to directly which they are triggered allows directed therapy to begin.
stimulate the CTZ. This effect appears to be mediated by Therapy should not only include antiemetics, but also mea- 5-hydroxytryptamine type 3 (5HT3) and neurokinin type 1 sures to alleviate the cause of the symptoms, such as the pro- (NK1) receptors. Second, chemotherapy is thought to dam- age the GI mucosa and cause release of neurotransmittersincluding 5HT Nonpharmacological Therapy
3. This stimulates nausea and vomiting via pe- ripheral pathways mediated by vagal and splanchnic nerves.
Nonpharmacological therapy is an important first consid- Third, there appears to be some neurohormonal etiology to eration in the management of intractable nausea. Simple rec- these symptoms via alteration in arginine vasopressin and ommendations like avoiding strong smells or other nausea prostaglandin levels.29 Finally, chemotherapy-induced nau- triggers, eating small, frequent meals, and limiting oral in- sea and vomiting may be mediated by anxiety, which can take during periods of extreme emesis are helpful.34,35 Psy- trigger symptoms via central pathways.30,31 chological techniques, especially those that promote relax- Malignant Bowel Obstruction. Malignant bowel obstruc-
ation, can be helpful.36,37 Acupuncture and acupressure may tion can occur with any malignancy but is most commonly provide some benefit in the setting of chemotherapy or sur- associated with advanced ovarian and colorectal cancer.32 gery. A systematic review found benefit to P6 stimulation Peripheral pathways are stimulated because of the stretch (just above the wrist) in 11 of 12 randomized placebo- of bowel wall, pain, and colic associated with accumulat- controlled trials.38 Acupressure wrist bands, however, have ing food and fluids proximal to the obstruction. Addition- not been shown to be effective.39 Medical devices includ- ally, the CTZ is likely triggered by inflammatory mediators ing gastric electrical stimulation40 and transcutaneous elec- trical nerve stimulation units41 are currently under inves- Impaired GI Tract Motility of Advanced Cancer. Auto-
tigation, but a lack of convincing evidence and substantial nomic dysfunction may play a central role in chronic nau- sea and vomiting in patients with advanced cancer as a re-sult of gastroparesis and constipation.33 Symptoms are likely Pharmacological Therapy
triggered by activation of peripheral pathways due to stretch A mechanism-based treatment scheme administering the of the gastric or esophageal wall from this poor motility. The most potent antagonist to the implicated receptors has been etiology of autonomic failure in patients with advanced can- shown to be effective in up to 80% to 90% of patients near cer is multifactorial, including malnutrition and cachexia, the end of life.9,10,42 It should be noted that some practition- chemotherapy and other drugs, radiation therapy, paraneo- ers recommend starting an empirical antiemetic regimen, plastic phenomena, nerve invasion by tumor, and comor- typically with a D2 antagonist, regardless of the presumed etiology.43 To date, no head-to-head comparisons between Mr Q’s esophageal irritation due to tumor burden and post- mechanism-based and empirical therapy exist.44 We advo- stent reflux is likely triggering nausea via vagal input into cate and practice a mechanism-based management para- the vomiting center. The opioids he is receiving may be ac- digm because it facilitates a systematic approach to caring tivating central D2 receptors in the CTZ, and the capecitab- for the patient, identifies all potential symptomatic con- ine chemotherapy may be activating NK1 receptors in the tributors, directs therapy, and minimizes the risk of over- CTZ and 5HT3 receptors in the GI tract and the CTZ.
In practice, multiple etiologies are often at play and pa- TREATMENT
tients are acutely symptomatic on presentation, requiring DR O: We generated a list of possible etiologies and tried to empirical treatment and numerous interventions while evalu- rank them. . . . We recommended adding [prochlorperazine] ation is ongoing. All potential underlying causes, such as to cover the possibility that the opiates were producing the nau- constipation, opioids, and electrolyte abnormalities should sea. Because of the possibility that he was having esophageal be addressed simultaneously to provide the greatest chance candidiasis, we recommended nystatin. Because of the stent and of rapidly resolving symptoms. When choosing antiemet- the possibility that reflux was creating irritation in his esopha- ics for these patients, we favor initiating medications that gus and upper GI tract, we thought about [adding sucralfate]. target the D2 receptor, such as metoclopramide, prochlor- 1200 JAMA, September 12, 2007—Vol 298, No. 10 (Reprinted)
2007 American Medical Association. All rights reserved.
MANAGEMENT OF INTRACTABLE NAUSEA AND VOMITING perazine, or haloperidol, which are the foundation of many first-line antiemetics are prescribed on an as-needed basis of the empirical schemes.43,45-47 Choosing one of these agents instead of scheduled around-the-clock.11 If nausea and vom- makes mechanistic sense because D2 antagonists block CTZ- iting continue despite effective blocking of the targeted path- mediated nausea, a common cause of symptoms in pa- way, a second agent that antagonizes other implicated neu- rotransmitters should be added. Adding a second agent is Another important consideration when selecting an an- preferred to switching agents because nausea is often mul- tiemetic is the medication’s adverse-effect profile. For ex- tifactorial and several neurotransmitters are active at each ample, a patient with nausea due to stimulation of the CTZ receptor site. This approach has proved effective in chemo- may benefit from either a 5HT3 or D2 antagonist. If the pa- therapy48 and for patients at the end of life.43,55-57 tient is concerned about excessive sedation, the clinician Prophylactic dosing prior to known emetogenic triggers might avoid the D2 antagonist, whereas, if constipation has has value particularly with chemotherapy,48 radiation been particularly problematic, the D2 antagonist might be therapy,17 in the postoperative setting,58 or in patients with known prior adverse reactions to, eg, opioids.59 Prevention A recent development is the incorporation of 5HT3 an- of nausea is particularly important if the stimulus is likely tagonists such as ondansetron. Evidence supports the use to be repeated, such as with chemotherapy, because of the of these agents for chemotherapy-induced nausea and vom- high potential for developing learned responses.30 iting,48 radiation therapy-induced nausea,49 and postopera- In the case of Mr Q, a careful evaluation revealed several tive nausea.50 Smaller studies suggest efficacy of 5HT3 an- possible contributory etiologies. As such, Dr O recom- tagonists in nausea and vomiting due to opioids51 and mended prochlorperazine to block D2 receptors in the CTZ uremia.52 However, the literature does not support using these to counteract nausea and vomiting due to opioids. In addi- agents empirically outside of the noted clinical scenarios.
tion, Dr O recommended lansoprazole and sucralfate to treat Moreover, for the most common etiologies of nausea and vomiting at the end of life, 5HT3 antagonists are no more In the following section, we apply the mechanistic ap- effective than the less expensive D2 antagonists.53,54 proach to the management of some of the most common eti- Despite evidence supporting its use, a mechanism-based ologies of nausea and vomiting in patients near the end of life monotherapy approach may not reduce nausea and vomit- (TABLE 2). TABLE 3 provides a list of frequently used anti-
ing to an acceptable level.9 Before changing regimens, prac- emetics, their mechanism of action, dosage, common ad- titioners should ensure that the prescribed therapy was verse effects, and cost. TABLE 4 reviews selected studies sup-
properly administered. A common management pitfall is that porting the use of these agents in patients near the end of life.
Table 2. Common Clinical Scenarios Associated With Nausea and Vomiting at the End of Life
Clinical Scenario
References
Mechanism of Nausea and Vomiting
Typical First-line Antiemetics
Constipation (H1, muscarinic acetylcholine Sensitization of labyrinth (H1, muscarinic dexamethasone (also consideroctreotide or hyoscyamine,nasogastric tube, ventinggastrostomy tube) 5HT3 released from enterochromaffincells in GI tract activate meningeal mechanoreceptors,which stimulate the vomiting center Abbreviations: CTZ, chemoreceptor trigger zone; D2, dopamine type 2 receptor; GI, gastrointestinal; H1, histamine type 1 receptor; ICP, intracranial pressure; NK1, neurokinin type 1 receptor; 5HT3, 5-hydroxytryptamine type 3 receptor.
2007 American Medical Association. All rights reserved.
(Reprinted) JAMA, September 12, 2007—Vol 298, No. 10 1201
MANAGEMENT OF INTRACTABLE NAUSEA AND VOMITING Opioid-induced Nausea and Vomiting
onstrates efficacy in both prospective and retrospective Generally, opioid-induced nausea and vomiting occurs with initiation of opioids or with dose escalation and resolveswithin 3 to 5 days of continued use. If nausea develops, an- Chemotherapy-Induced Nausea and Vomiting
tiemetics targeting D2 receptors should be prescribed around- The patient’s goals of care are paramount when consider- the-clock for several days and then tapered as tolerated.24,70 ing the use of chemotherapeutic agents near the end of life.
Haloperidol, droperidol,46,59,71 and metoclopramide59,72 all Management of chemotherapy-induced nausea and vomit- have demonstrated efficacy. Limited evidence suggests that ing is preventive and based on the emetogenicity of the pre- promethazine may potentiate the effects of opioids.73 Al- scribed agent (TABLE 5).48
though some clinicians see this interaction with opioids as Some of the nausea associated with chemotherapy may a therapeutic advantage, others avoid promethazine due to also be anxiety-related or “anticipatory” because patients as- sedation and the increased risk of respiratory depression.74 sociate receiving chemotherapy with becoming nause- A small number of patients develop persistent nausea that ated.37 This may partially explain the observed decreasing may improve with an opioid dose-reduction or rotation. A efficacy of antiemetics in patients undergoing multiple cycles 10% to 20% reduction in daily opioid dose often alleviates of chemotherapy.78 Although not strictly classifiable as an- nausea without a loss in analgesia.75 However, if dose re- tiemetics, benzodiazepines such as lorazepam are effective duction is not feasible or is ineffective, opioid rotation dem- in preventing anticipatory nausea.79,80 Outside of this set- Table 3. Antiemetics
Presumed Primary
Antiemetic
Trade Name
Receptor Site of Action
Dosage/Route
Major Adverse Effects
Abbreviations: CTZ, chemoreceptor trigger zone; D2, dopamine type 2 receptor; GI, gastrointestinal; H1, histamine type 1 receptor; IM, intramuscular; IV, intravenous; 5HT3, 5-hydroxy- a Ondansetron is included as an example of 5HT3 antagonists because it was the first agent of this class and adopted in many hospital formularies. Its inclusion is not meant to indicate superiority over other members of the class, such as dolasetron, granisetron, and palonosetron.
b Cost per pill was calculated from prices listed on epocrates.com.
1202 JAMA, September 12, 2007—Vol 298, No. 10 (Reprinted)
2007 American Medical Association. All rights reserved.
MANAGEMENT OF INTRACTABLE NAUSEA AND VOMITING ting, however, the use of benzodiazepines for nausea is gen- is associated with a high complication rate.84 Gastrointes- tinal tract stents may have a role, depending on the loca-tion of the obstruction, but have been associated with com- Malignant Bowel Obstruction
plications.85 Nasogastric tubes can relieve symptoms but Management of malignant bowel obstruction often in- should only be used temporarily while other treatment is volves both pharmacologic and nonpharmacologic inter- pursued given the complications and discomfort associ- ventions. Surgery is generally not recommended for per- sons with a life expectancy of less than 2 months82,83 because Fortunately, medical management provides very effective it does not improve survival, rarely palliates symptoms, and symptom control.86 Recommended pharmacologic therapy in- Table 4. Selected Studies Supporting Use of Common Antiemeticsa
Length of
Intervention
Design Participants
Outcomes
Follow-up
Adverse Events
prochlorperazine(P value range, .07-.08) 2007 American Medical Association. All rights reserved.
(Reprinted) JAMA, September 12, 2007—Vol 298, No. 10 1203
MANAGEMENT OF INTRACTABLE NAUSEA AND VOMITING Table 4. Selected Studies Supporting Use of Common Antiemeticsa (cont)
Length of
Intervention
Design Participants
Outcomes
Follow-up
Adverse Events
Abbreviations: IM, intramuscular; IV, intravenous; RCT, randomized controlled trial; VAS, visual analog scale.
a Study selection based primarily on quality of evidence and secondarily on how well the study population approximates patients near the end of life.
b Statistically significant at P Ͻ .05.
as haloperidol, which work primarily at the CTZ. Antihista- Table 5. American Society of Clinical Oncology Guidelines for
mines that work through peripheral pathways and the vom- Management of Chemotherapy-Induced Nausea and Vomitinga iting center may also be effective. Corticosteroids, such as dexa- Incidence
of Emesis Without
methasone, are generally included in most antiemetic regimens Risk Category
Antiemetics, %
Antiemetic Regimen
for their potential effect on tumor-associated inflammation.
A recent Cochrane review found a nonsignificant (PϾ.05) trend suggesting that corticosteroids may be effective in helping re- If medical therapy provides insufficient relief, a venting gastrostomy tube may be placed. With this, gastrointesti- nal and oral secretions are removed without a nasogastric tube, and the patient may continue liquid oral intake as de- Intractable Nausea and Vomiting
Abbreviation: 5HT3, 5-hydroxytryptamine type 3 receptor.
MR Q: We tried these little dots [ondansetron ODT] for nau- sea. But nothing was working. It wasn’t until we went into thehospital and just started experimenting that I really got some cludes analgesics, antisecretory agents, and antiemetics.32 Opi- oids are used for pain control. Anticholinergics such as hyo- In some cases, nausea and vomiting may persist despite a scyamine and a somatostatin analogue (octreotide) diminish mechanism-based approach using several medications at secretions and potentially reduce pain and nausea by decreas- appropriate dosages taken around-the-clock targeting mul- ing mucosal distention and peristalsis. Octreotide can be ad- tiple pathways. In these situations, less traditional agents ministered subcutaneously beginning at 50 to 100 µg 3 times can be considered, but evidence supporting their use daily (to a maximum of 900 µg per day). Some palliative care remains limited. For instance, dexamethasone, is widely units will administer octreotide via continuous infusion at much used for its antiemetic effects in palliative care, even though higher doses, although evidence to support this practice is a recent study demonstrated no greater effect than placebo scarce. Metoclopramide is recommended for patients with nau- when added to metoclopramide for patients with chronic sea and a partial obstruction without colic. In patients with nausea of advanced cancer.90 Despite this study’s results, complete obstruction, metoclopramide can induce colic corticosteroids have well-described antiemetic properties,91 through its peripheral D2 receptor stimulation of GI motility, and in our experience are extremely effective at decreasing although this concern may be overstated.87 For these pa- symptom severity. Mirtazapine, an antidepressant that tients, the recommended agents are central D2 antagonists, such antagonizes the 5HT3 receptor, is also frequently used to 1204 JAMA, September 12, 2007—Vol 298, No. 10 (Reprinted)
2007 American Medical Association. All rights reserved.
MANAGEMENT OF INTRACTABLE NAUSEA AND VOMITING alleviate intractable symptoms. To date, evidence support- taking prochlorperazine and haloperidol, both of which work ing its use is limited to small trials and case reports.68,92 on the D2 receptor, the risk of a dystonic reaction or aka- Cannabinoid agents, such as dronabinol, can be effective thisia increases. A mechanism-based approach helps avoid antiemetics in patients with AIDS93,94 and cancer95,96 but this pitfall and facilitates a step-wise introduction of medi- s h o u l d b e u s e d w i t h c a u t i o n i n o l d e r a d u l t s o r cations that exert their effects at different receptor sites.
cannabinoid-naive patients because adverse effects, includ-ing confusion and hallucinations, may be pronounced.
Palliative Sedation
Olanzapine, an atypical antipsychotic, blocks several recep- If nausea and vomiting remain intractable despite aggressive, tors associated with nausea and vomiting including dopa- multimodal attempts at control, palliative sedation may be con- mine, acetylcholine, histamine, and serotonin receptors.
sidered for patients with a limited life expectancy.115,116 Al- Larger studies are needed to better define its role.97-99 though symptoms of nausea and vomiting are rarely the pri- Megestrol acetate and thalidomide decreased nausea in mary indication for palliative sedation,117 they are commonly patients enrolled in clinical trials for appetite stimula- noted secondary symptoms of patients choosing palliative se- tion,100,101 but they are rarely used solely for their antiemetic dation for other reasons (36%-44% of cases).115 No standard properties. The ABHR suppository, a combination prepara- regimen exists for sedation of patients with intractable nau- tion of lorazepam (Ativan), diphenhydramine (Benadryl), sea; however, propofol has been proposed as an ideal agent haloperidol (Haldol), and metoclopramide (Reglan), is because it blocks 5HT3 receptors, resulting in an antiemetic often used for home hospice patients, although there are no effect in addition to its sedative effects.118 data to support its benefit. It is well tolerated,102 but, in ourexperience, exerts its effect mainly through sedation.
CONCLUSIONS
Herbal medicines have been used to treat chemotherapy- A step-wise, mechanism-based approach to treatment of nau- induced103 and pregnancy-induced104 nausea and vomiting, sea and vomiting has proved effective for a majority of pa- but little evidence exists to support their use in end-of-life tients experiencing these symptoms toward the end of life.
populations.105 Finally, 5HT3 antagonists are sometimes A thorough assessment to ascertain potential etiologies, path- used to treat intractable nausea and vomiting,106-108 but, as ways, and respective transmitters and receptors allows the noted above, there is little justification for their use outside clinician to prescribe the most appropriate antagonist to the of circumscribed clinical scenarios.
offending receptor. If monotherapy is ineffective, a trial com- Refractory nausea and vomiting may make oral admin- bining several therapies to block multiple emetic pathways istration of medication unfeasible so alternate routes must is recommended. Further research will refine palliative care be considered. Many of the most common antiemetics are management strategies that minimize adverse effects and available in several preparations, such as rectal supposito- maximize control of these highly distressing symptoms.
ries, subcutaneous infusions,109 and orally dissolvable tab- Author Affiliations: Department of Medicine, Division of Hematology/
lets (Table 3), allowing patients to be treated at home.
Oncology, Feinberg School of Medicine, Northwestern University, Chicago, Illi-nois (Drs Wood, Shega, and Roenn and Ms Lynch). Dr Wood is now with the De- Polypharmacy and Drug-Drug Interactions
partment of Medicine, Division of General Internal Medicine, Section of PalliativeCare and Medical Ethics, Institute to Enhance Palliative Care, University of Pitts- DR O: Ordinarily, I like to do things one at a time. If you do a burgh School of Medicine, Pittsburgh, Pennsylvania.
Financial Disclosures: None reported.
bunch of things at once, you never know what the useful things Funding/Support: The Perspectives on Care at the Close of Life section is made
were. . . . I was a little nervous that the medical team was using possible by a grant from the Archstone Foundation.
such a variety of antinausea medicines. Role of the Sponsor: The funding source had no role in the preparation, review,
or approval of the manuscript.
Avoiding polypharmacy is a critical aspect of nausea and Other Sources: For a list of relevant Web sites, see the article on the JAMA Web
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Web Resources for End-of-Life Care
End of Life/Palliative Education
m a n a g e m e n t o f c h e m o t h e r a p y - Resource Center
NATIONAL CANCER INSTITUTE
(NCI) SUPPORTIVE CARE:
AMERICAN SOCIETY OF
NAUSEA AND VOMITING
CLINICAL ONCOLOGY (ASCO)
GUIDELINE FOR ANTIEMETICS
PALLIATIVE CARE LEADERSHIP
IN ONCOLOGY: UPDATE 2006
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