Nausea and Vomiting in Palliative Care Patients Dr Nial

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Nausea and Vomiting in Palliative Care Patients

• Dr Nial McCarron
• ST5 Palliative Medicine
• UHB

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Objectives

• Definitions and prevalence
• review mechanisms/physiology of nausea and
  vomiting
• review possible causes of nausea/vomiting in
  palliative patients
• understand rationale behind selecting specific
  anti-emetics
• develop a systematic approach to managing nausea
  and vomiting

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Definitions of Nausea and Vomiting

• Nausea is an unpleasant sensation of the need to
  vomit, which is often accompanied by autonomic
  symptoms (e.g. pallor, cold sweat, salivation,
  and tachycardia) Twycross and Wilcock,
  2001 Kinley, 2005.
• Retching Non productive attempt to vomit
• a strong, involuntary effort to vomit, which
  usually occurs in the presence of nausea. It
  involves movement of the diaphragm and abdominal
  muscles against a closed glottis Twycross and
  Wilcock, 2001 Kinley, 2005.

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Definitions..

• Vomiting (emesis) is the forceful ejection of
  stomach contents through the mouth. The diaphragm
  and abdominal muscles contract and increase
  intra-abdominal pressure, compressing the
  stomach. The stomach, oesophageal sphincter, and
  pylorus relax, allowing reverse peristalsis and
  forcing the stomach contents upwards Twycross
  and Wilcock, 2001 Kinley, 2005 Perdue, 2005.
• Intractable nausea
• Nausea and vomiting not adequately controlled
  after multiple antiemetics are used in series and
  combinations
• Anticipatory nausea
• Nausea and vomiting occurring as a result of a
  conditioned response from previous treatment

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Nausea and Vomiting in Palliative Care

• Occurs in 62 of terminally ill cancer patients
• At least 40 report nausea and vomiting in the
  last six weeks of life
• Up to 25 of cancer patients being treated for
  pain also reported nausea
• Causes psychological distress for patients and
  families
• Contributes to fears about starvation,
  dehydration and disease progression
• Significantly affects quality of life, compliance
  with treatment and health care cost

Arch Int Med. 1986146(10)2021-2023
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Pathophysiology

• Chemoreceptor Trigger Zone (CTZ) Area Postrema
• outside blood-brain barrier
• Exposure to toxins (endogenous or exogenous) in
  the bloodstream or CSF stimulates the vomiting
  center
• Cerebral Cortex
• Gains imput from the senses, meningeal irriation
  and increased ICP that activate vomiting center
• Peripheral pathways
• GI and viscera mechano- and chemoreceptors
  transmit messages via the vagus and splanchnic
  serves, sympathetic ganglia and glossopharyngeal
  nerves
• Vestibular System
• Nausea and vomiting triggered by motion

JAMA 2007298(10)1196-1207
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Pathophysiology
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Treatment Approach

• Evaluate the most likely aetiology of the
  patients nausea and vomiting
• Use pathophysiology knowledge to determine the
  likely mechanism and involved receptors
• Choose appropriate therapy to target these
  receptors

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Evaluation of Aetiology

• History of present illness
• Have you had persistent nausea, vomiting or both?
• Is the nausea constant?
• Does nausea always lead to vomiting?
• Does vomiting occur without nausea?
• Do the symptoms occurs when you take certain
  medications or when you eat?
• Are you aware of any triggers?
• What have you taken for the nausea and/or
  vomiting and has it worked?
• When was your last bowel movement?

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Evaluation of Aetiology

• Complete medication history
• Chemotherapy, opioids, antidepressants and
  antibiotics
• Non-pharmacological therapies
• Radiation and surgery
• Past medical history
• Diabetes, alcoholism, CRF, autoimmune disorders,
  amyloidosis and Parkinsons can all cause delayed
  gastric emptying and autonomic dysfunction

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Evaluation of Aetiology

• Physical examination
• Abdominal, rectal, and neurological exam
• With the person and their carers and family,
  determine what investigations are appropriate for
  the person's stage of illness
• Blood tests to exclude hypercalcaemia and uraemia
  are among the most useful investigations in all
  people with nausea or vomiting in a palliative
  care situation in primary care.
• Radiological investigations eg abdominal
  radiography to exclude constipation or intestinal
  obstruction, ultrasonography to detect ascites.

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Common Causes in Cancer Patients

• Constipation
• Liver metastases
• Malignant bowel obstruction
• External compression of stomach or intestines by
  tumor
• Primary or metastatic brain or leptomeningeal
  disease
• Pain medications

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Table 1. Causes of nausea and vomiting in people
receiving palliative cancer care
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Common Causes Constipation

• One of the most common causes of nausea and
  vomiting in patients with end-stage cancer
• Decreased fluid and food intake
• Drug therapy including chemotherapy and opioids
• Hypercalcaemia and/or hyponatraemia
• Tumor compression of the bowel or invasion of the
  visceral abdominal muscles
• Autonomic dysfunction
• Pathophysiology
• Slowing of intestinal peristalsis
• Increased abdominal pressure and distention of
  bowel
• Activation of gut neurotransmitters

ANJ. 2004104(11)40-48
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Common Causes Bowel Obstruction

• Most common in advanced abdominal or pelvic
  cancers
• Up to 42 in advanced ovarian cancer
• Up to 29 in advanced colorectal cancer
• Patient commonly presents with nausea, vomiting,
  and pain of gradual onset
• Tumor externally compresses the bowel or grows
  into the bowel lumen
• Peripheral pathways are stimulated because of
  tissue stretching
• CTZ is activated by inflammatory mediators and
  bacterial toxins

ANJ. 2004104(11)40-48
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Common Causes

• Brain involvement of tumors
• Growth of cancer in the brain is sensed by local
  pressure receptors (?histaminergic)
• Activation of the vomiting center
• Drug therapy Opioids
• Decrease GI peristalsis via gut opioid receptors
• Activation of CTZ by central dopamine type 2
  receptors
• Exacerbated by impaired hepatic metabolism and
  renal excretion in patients with end-stage
  cancer?

ANJ. 2004104(11)40-48
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What are the complications of nausea and vomiting

• Dehydration and electrolyte imbalance (metabolic
  alkalosis in severe vomiting).
• Decreased nutrition leading to nutritional
  deficiencies.
• Aspiration pneumonia.
• Oesophageal tears.
• Decreased ability to self care.
• Decreased quality of life and psychological and
  social well-being.
• Thompson, 2004 Cancer Care Ontario,
  2005 Perdue, 2005

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Simple management

• Make sure the person has access to a large bowl,
  tissues, and water.
• The sight and smell of food or drink may provoke
  nausea
• Provide the person with a calm environment away
  from where food is usually prepared or consumed.
• If the person is usually responsible for cooking,
  make alternative arrangements.
• Make sure meals are small and palatable.
• Carbohydrate meals are often better tolerated.
• Offer cool, fizzy drinks (citrus flavours are
  often preferred).

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Simple management

• Consider parenteral hydration if appropriate (in
  all people but those at the very end of life).
• Consider the use of complementary therapies
  relaxation and acupressure bands may be useful to
  relieve symptoms.
• Consider the use of cognitive behavioural therapy
  for anticipatory nausea or vomiting.
• In general, avoid nasogastric suction.

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General points

• Ascertain the most appropriate route of
  administration of the anti-emetic.
• Prescribe anti-emetics regularly and as required.
• Review the effectiveness of anti-emetic treatment
  every 24 hours.
• Continue use of anti-emetics unless nausea and
  vomiting has resolved (e.g. the cause was
  self-limited or has been reversed).

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A mechanism-based treatment scheme administering
the most potent antagonist to the implicated
receptors has been shown to be effective in up to
80-90 of patients near the end of life
JAMA 2007298(10)1196-1207
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Classes of Antiemetic Agents

• Anti-histamines
• Serotonin Antagonists
• Corticosteroids
• NK1 Receptor Antagonist (i.e. Aprepitant)
• Dopamine antagonists
• Metoclopramide
• Phenothiazines (i.e. Prochloroperazine)
• Butyrophenones (i.e. Haloperidol)
• Benzodiazepines
• Cannabinoids (i.e. Marinol)

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CYCLIZINE

• Antihistiminic (H1) anti-muscarinic
• Acts on receptors in the vestibular and vomiting
  centres
• NB anticholinergic effect on the bowel
• Onset of action lt 2 hours
• Duration of action 4-6 hours
• Plasma halflife 5 hours
• Adverse effects
• Drowsiness
• Antimuscarinic effects
• Skin irritation with CSCI
• NB Detrimental haemodynamic effects in heart
  failure increases arterial and ventricular
  filling
• pressures, negating venodilatory effects of
  diamorphine (Tan 1988)
• Usual Dose
• Usual maximum daily dose 150mg, PO or CSCI
• Use
• in bowel obstruction, raised intracranial
  pressure and
• movement induced nausea and vomiting.

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Serotonin AntagonistsOndansetron, Granisetron,
Dolasetron, Palonosetron
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Serotonin AntagonistsOndansetron, Granisetron,
Dolasetron, Palonosetron

• Mechanism of action
• Block serotonin receptors in the GI tract
• Effective at preventing acute emesis after
  chemotherapy, radiation and anesthesia
• Clinical considerations
• Equal safety and efficacy at equivalent doses
• Single dose regimens have equal efficacy to
  multidose regimens
• Oral and IV routes are equivalent
• Adverse Effects headache, constipation, reduced
  efficacy of paracetamol

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Dexamethasone

• Mechanism of Action unknown
• Inhibition of prostaglandin synthesis?
• Decreased BBB permeability of chemotherapy agents
• Inhibition of cortical input to vomiting center
• Place in therapy
• Brain tumour or CNS involvement
• Malignant bowel obstruction
• Chemotherapy induced nausea and vomiting
• Generally well tolerated
• Fluid retention, restlessness, insomnia,
  hypertension
• Watch blood glucose in diabetic patients

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NK1 Receptor Pathway
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NK1 Receptor AntagonistAprepitant (Emend)

• Competitively antagonizes the NK1 receptors
• Place in therapy
• Approved for the prevention of acute and delayed
  nausea and vomiting following cisplatin and CA
  containing regimens
• Improves acute emesis control when combined with
  5HT3 antagonist plus dexamethasone
• Extensive metabolism through CYP450 system
• FDA Approved Dosing
• 125 mg PO day 1, 80 mg PO days 2 and 3

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NK1 Receptor AntagonistAprepitant (Emend)

• PRECAUTION
• EMEND should be used with caution in patients
  receiving concomitant medicinal products that are
  metabolized through CYP3A4 some chemotherapy
  agents are metabolized by CYP3A4
• Other clinical considerations
• Reduces (S)-warfarin levels (induction of CYP2C9)
• Reduces levels of OC (ethinyl estradiol 40
  decrease) with 2 week dosing
• Increases AUC ratio of dexamethasone by 2.2 fold

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Metoclopramide

• Mechanism of action
• Prokinetic
• Dopamine antagonist (D2)
• 5HT4 agonist (most important activity)
• 5HT3 antagonist (gt100mg/24 hrs)
• Place in Therapy
• Opioid-induced nausea and vomiting
• Malignant bowel obstruction (if incomplete)
• Impaired GI motility
• Adverse effects
• Extrapyramidal
• Acute dystonic reactions and oculogyric crisis
• Restlessness
• Diarrhoea
• Colic
• Neuroleptic malignant syndrome

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Phenothiazine Dopamine AntagonistsLevomepromazine
(Prochloroperazine)

• Broad spectrum of activity D2, 5HT2 , alpha 1,
  H1 and A Ch muscarinic antagonism
• Block dopamine receptors in the CTZ
• Place in therapy
• Opioid-induced nausea and vomiting
• Delayed nausea due to chemotherapy
• Resistant NV
• Adverse effects
• Sedation (tx decrease dose)
• Extrapyramidal effects (tx diphenhydramine)
• Akathysia (tx benzodiazepine)

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Other Dopamine AntagonistsHaloperidol and
Droperidol

• Block dopamine D2 receptors in CTZ
• Potential use in breakthrough and/or refractory
  N/V after trying other agents
• Less effective than metoclopramide as prokinetic
• More effective for Opiate induced nausea
• Adverse effects
• Sedation, dystonia, akasthesia
• Droperidol Black box warning-QT prolongation

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Benzodiazepines

• Not true antiemetic agents
• Amnestic properties reduce incidence of
  anticipatory emesis
• Place in therapy
• Combined with 5HT3 antagonists and dexamethasone
  for anxiolytic and amnestic effects
• Mitigates metoclopramide-induced agitation
• Lorazepam 1-2mg prior to chemotherapy, followed
  by 1mg q 6 -12 hr

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Canabinoids

• Unknown mechanism of action
• Believed to act on CTZ and NTS, possible
  substance P
• Effective predominantly as an adjunctive agent
• Dosing
• Marinol 5 10mg/m2 po q 3 - 4 hr
• CIII controlled substance
• Adverse effects
• Sedation, dizziness, hypotension, dysphoria

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Opioid-Induced

• Seen in up to 40 of patients receiving opioids
• Often resolves after 3-5 days of repeat dosing
• Pathophysiology
• Decrease GI peristalsis via gut opioid receptors
• Activation of CTZ by central dopamine type 2
  receptors
• Drugs of choice Dopamine antagonists
• Metoclopramide
• Haloperidol

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Chemotherapy induced (CINV)
American Society of Clinical Oncology 2006 (J
Clin Oncol. 2006242932-2947)
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2006 ASCO Recommendations for Specific Emetic
Risk Categories Chemotherapy-Induced Acute Emesis
Source ASCO (American Society of Clinical
Oncology Version 5/22/06
American Society of Clinical Oncology 2006 (J
Clin Oncol. 2006242932-2947)
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Malignant Bowel Obstruction

• Pathophysiology
• Peripheral pathways are stimulated
• CTZ is activated by inflammatory mediators and
  bacterial toxins
• Therapy of choice
• Surgery only recommended if life expectancy is gt
  2 months
• Nasogastric tubes for temporary management
• Opioids for pain control
• Anticholingerics (hyoscine or octreotide)
• Metoclopramide (if not complete obstruction)
• Haloperidol (also can treat pain and reduce
  secretions)
• Dexamethasone (may help resolve obstruction)
• Venting gastrostomy tube

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Intractable Nausea/Vomiting

• Pathophysiology
• Sometimes what we think should works, doesnt
• Different in every patient
• Drugs of choice
• Combination therapy targeting different receptors
• Dosing of drugs around the clock (ATC), not prn
• Dexamethasone
• Mirtazepine, cannabinoids, olanzapine
• Use of oral disintegrating tablets (ondansetron),
  intravenous or rectal formulations may be required

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Motion-Associated

• Pathophysiology
• Vestibulocochlear nerve stimulation
• Receptors muscarinic acetylcholine and histamine
• Drugs of choice
• CYCLIZINE 25-50mg tds
• Scopolamine patch 1.5 mg TD q3 days
• Promethazine 12.5-25 mg PO q6h
• Diphenhydramine 25-50 mg PO q6h