Final PDF Version

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Final PDF Version

• For posting on web

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A Simpler Approach to the Management of Nausea
Vomiting (at the End-of-Life)

• Andrew C Knight, MD
• April 19, 2010
• Ontario Hospice Palliative Care Conference -
  Toronto

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Disclosure

• Dr Andrew Knight perceives no conflict of
  interest with this presentation and has
  previously received speaker honoraria from the
  following companies
• Purdue Pharma
• Wyeth
• Paladin Labs
• Jansen-Ortho
• Sanofi-Aventis

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Objectives

• Nausea Vomiting
• select anti-emetics appropriate to the
  underlying condition
• apply a systematic approach in the management of
  nv_at_eol
• Bowel Obstruction ( ascites)
• recognition management (as a contributing
  cause to nv_at_eol)

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Goals of Care

• .
• ..
• treat symptom effectively
• minimize toxicity

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Evidence Based Medicine

• problematic in terminally ill
• excluded from clinical trials
• borrow evidence from other patient groups
• rely on anecdotal experience
• expert opinion
• only one chance to get it right

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Anti-emetics
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Anti-emetics

• MASCC - ANTIEMETIC GUIDELINES - latest
  update March 2008
• ASCO Use of anti-emetics
  updated 2006
• advanced cancer - information void

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Pathogenesis CINV
From G Fyles, 10/08
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Dimenhydrinate (Gravol)

• 1949
• only available over-the-counter anti-emetic
• combination of diphenhydramine (Benadryl)
  8-chlorotheophylline
• dimenhydrinate 50 mg diphenhydramine 27.5 mg

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Diphenhydramine (Benadryl)

• 1946
• histamine-1 antagonist (H1)
• muscarinic antagonist (M1)
• 1960s serotonin antagonist (5HT2)
• ? development of fluoxetine (Prozac)
• moderate inhibitor of CYP 2D6

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• Twycross Back, Nausea Vomiting in Advanced
  Cancer, European Journal of Palliative Care,
  1998 5 (2), pp 39-45.
• summary of consensus workshop guidelines
• 5th Congress, European Association for Palliative
  Care, London, 1997

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Neurophysiology

• cerebral cortex
• chemoreceptor trigger zone (CTZ)
• vestibular apparatus
• gastrointestinal tract
• vomiting centre

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Neurophysiology of Nausea Vomiting
Cerebral Cortex GABA, CB1
Chemoreceptor Trigger Zone D2, 5HT3, NK-1
Vomiting Centre H1, M1, 5HT2, NK-1
Gastrointestinal Tract D2, 5HT3, 5HT4
Vestibular Apparatus H1, M1
Adapted from G Fyles, 2008
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Cerebral Cortex

• psychological, social spiritual issues
• experience of total pain
• anxiety
• anticipatory nausea
• receptors
• ?-amino-butyric acid (GABA)
• cannabinoid (CB1)

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Cerebral Cortex

• benzodiazepines (lorazepam)
• cannabinoids
• dronabinol (Marinol) 2.5, 5, 10 mg capsules
• dose 5 mg/m2 pre then q2-4h (4-6 doses / 24h)
• nabilone (Cesamet) 0.25, 0.5, 1 mg capsules
• dose 1-2mg BID max 6 mg / 24h
• caution in elderly

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Intracranial Disease

• primary brain tumour
• metastatic disease
• leptomeningeal disease
• vasogenic edema, ? intracranial pressure
• ? ? stimulation of vomiting centre (VC)
• steroids (dexamethasone)
• radiation
• antihistamine (VC antagonist)

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Chemoreceptor Trigger Zone

• floor of 4th ventricle (CSF blood poorly
  developed blood-brain barrier)
• toxins (ETOH)
• drug opiates, digoxin, chemotherapy
• metabolic renal failure, hypercalcemia
• infections bacterial, viral
• receptors
• dopamine (D2)
• serotonin (5HT3)
• neurokinin-1 (NK-1)

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NK-1 Receptor

• distribution CTZ vomiting centre
• neurotransmitter substance P
• antagonist aprepitant (Emend)
• highly emetogenic chemotherapy only
• 400 for 3 day course of therapy
• no established role in palliative care

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Vestibular Apparatus

• motion-induced nausea
• vertigo
• receptors
• histamine (H1)
• muscarinic (M1)

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Gastrointestinal Tract / Abdomen

• vagus nerve
• enterochromaffin cells
• chemoreceptors mechanoreceptors
• malignant tumours
• bowel distension/ obstruction/ constipation
• radiation
• receptors
• dopamine (D2)
• serotonin (5HT3 5HT4)

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Vomiting Centre

• inter-related neuronal networks (medulla)
• final common pathway
• receptors
• histamine (H1)
• muscarinic (M1)
• serotonin (5HT2)
• neurokinin-1 (NK-1)

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Anatomic Distribution of Receptors
(Modified from Twycross Back, European Journal
of Palliative Care, 1998 5 (2), p 40.)
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Receptor Affinities of Selected Anti-emetics

(Modified from Twycross Back, European Journal
of Palliative Care, 1998 5 (2), p 41.)
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Case

• 35 yr ?
• paraplegia, paraspinal mass
• Bx granulocytic sarcoma
• bone marrow AML (M5)
• radiation T5-T12
• induction IDAC ? pancytopenia, diarrhea
• bowel rest, TPN

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Case

• nausea, episodic emesis develops following IDAC
  (Day 10)
• metoclopramide aggravated diarrhea ? stopped
• dimenhydrinate 50mg IV q6h started without
  improvement ? stopped

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Case

• haloperidol 1mg IV q8h diphenhydramine 25mg IV
  q6h
• relief within 24 hrs
• diphenhydramine ? to 25mg IV q8h
• no further nausea 2 wk, anti-emetics withdrawn,
  able to tolerate regular diet

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Anatomic Distribution of Receptors
Metoclopramide
(Modified from Twycross Back, European Journal
of Palliative Care, 1998 5 (2), p 40.)
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Anatomic Distribution of Receptors
Dimenhydrinate
(Modified from Twycross Back, European Journal
of Palliative Care, 1998 5 (2), p 40.)
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Anatomic Distribution of Receptors
Haloperidol
(Modified from Twycross Back, European Journal
of Palliative Care, 1998 5 (2), p 40.)
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Anatomic Distribution of Receptors
Haloperidol
Diphenhydramine
(Modified from Twycross Back, European Journal
of Palliative Care, 1998 5 (2), p 40.)
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The Approach

• an attempt to achieve broad simultaneous coverage
  of multiple receptors across several anatomic
  areas

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• prior to advent of 5HT3 antagonists, high
  dose metoclopramide (80mg / 24hr) used as
  anti-emetic
• akathesia often encountered
• diphenhydramine added to counter akathesia

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Anatomic Distribution of Receptors
Metoclopramide
Diphenhydramine
(Modified from Twycross Back, European Journal
of Palliative Care, 1998 5 (2), p 40.)
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• haloperidol / diphenhydramine combination may
  provide intrinsic anticholinergic protection
  against EPS / akathesis
• similar to documented experience with
  metoclopramide / diphenhydramine

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Dopamine-Acetylcholine Balance
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EPS Akathesia, Dystonic Drug Reactions, etc

• result of dopamine (D2) receptor blockade
• management includes anticholinergic agent
• may be less common with some agents due to
  intrinsic anticholinergic (muscarinic antagonist)
  activity
• avoid double coverage of D2 receptors

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What about sedation?

• appears to be an inherent consequence of H1 M1
  receptor blockade within CNS
• 2nd generation antihistamines - markedly reduced
  lipid solubility cross BBB poorly, ? not useful
  as anti-emetics

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Another scenario

• chemoreceptor trigger zone (CTZ)
• eg. renal failure

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Anatomic Distribution of Receptors
Haloperidol
(Modified from Twycross Back, European Journal
of Palliative Care, 1998 5 (2), p 40.)
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Anatomic Distribution of Receptors
Haloperidol
Diphenhydramine
(Modified from Twycross Back, European Journal
of Palliative Care, 1998 5 (2), p 40.)
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Anatomic Distribution of Receptors
Haloperidol
Diphenhydramine
Ondansetron
(Modified from Twycross Back, European Journal
of Palliative Care, 1998 5 (2), p 40.)
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The Simpler Approach

• consider underlying cause
• consider the relevant neuroanatomy receptors
  implicated
• select a drug with appropriate receptor coverage
• add a second and/or third agent in stepwise
  fashion
• avoid double coverage of D2 receptors
• remember the concept of total nausea

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by the ladder

• Step 1 D2 antagonist
• Step 2 add 1st generation anti-histamine
• (H1, M1
  5HT2)
• Step 3 add 5HT3 antagonist
• adjuvants benzodiazepines, canabinnoids,
  steroids - add as indicated

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(No Transcript)
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The Anti-emetic Staircase
Nausea
Add 5HT3 Antagonist
Nausea
Add Antihistamine
Nausea
D2 Antagonist
Nausea / Vomiting
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D2 Antagonists

• metoclopramide 10 - 20 mg po/ sc/ iv/ pr TID
  QID
• domperidone 10 20 mg po TID QID
• (does NOT cross BBB but does act at CTZ)
• haloperidol 0.5 2.5 mg po / iv / sc Q8-12H
• prokinetic agents

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What About the Atypicals?

• 2nd generation neuroleptics
• reduced incidence of EPS, etc
• olanzapine (Zyprexa, ZyprexaZydis)
• multiple publications support role as anti-emetic
  

Contents of above table extracted from Clinical
Handbook of Psychotropic Drugs, 16th Edition,
2006 p 108
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Anatomic Distribution of Receptors
Olanzapine

Olanzapine data from Clinical Handbook of
Psychotropic Drugs, 16th Edition, 2006 p 108.
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Anatomic Distribution of Receptors
Methotrimeprazine
Methotrimeprazine data from Clinical Handbook of
Psychotropic Drugs, 16th Edition, 2006 p 108.
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The Anti-emetic Staircase II
Freedom from Nausea
Add 5HT3 Antagonist
Nausea
2nd Generation Neuroleptic or Methotrimeprazine
Nausea / Vomiting
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Olanzapine

• dosing
• 2.5 5 mg po / sl / sc OD or BID
• Zyprexa 2.5, 5, 7.5, 10, 15, 20 mg tabs
• ZyprexaZydis 5, 10, 15, 20 mg oral
  disintegrating tabs
• ZyprexaIntraMuscular 10 mg / 5 ml single
  dose vial

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Methotrimeprazine

• Dosing
• 5 - 25 mg po or 6.25 - 25 mg sc Q8H
• Nozinan
• 25 mg / ml 1 ml amps
• 5, 25, 50 mg tabs

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Further Reading

• Twycross Back, Nausea Vomiting in Advanced
  Cancer, European Journal of Palliative Care,
  1998 5 (2), pp 39-45.)
• Fraser Health Hospice Palliative Care Program
  Symptom Guidelines Nausea Vomiting
• Pereira JL, Associates. The Pallium Palliative
  Pocketbook, 1st ed. The Pallium Project 2008.
• CCO Palliative Care Symptom Management Working
  Group Guide to Practice Nausea Vomiting
  coming soon

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Bowel Obstruction
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Bowel Obstruction

• often prior event
• most common colorectal, ovary
• clinical
• ? belching / ? flatus
• emesis bilious vs. feculent
• abdomen often distended tympanitic
• bowel sounds
• incomplete vs complete
• opiate / narcotic bowel syndrome

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Bowel Obstruction

• surgical options often limited
• focal vs diffuse metastatic disease
• life expectancy
• cachexia
• setting of care (home vs hospital)
• conservative approach often favoured

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Bowel Obstruction

• enteral fluid balance of oral intake, secretion
  absorption
• SBO may curtail substantial absorption distal to
  level of obstruction
• increased secretion in setting of SBO

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Bowel Obstruction The Vicious Cycle
James L Hallenbeck, Palliative Care
Perspectives, 2003 (On-line version)
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Management

• NG tube
• steroids
• anticholinergics
• octreotide

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NG Tube

• NG tube often best option most effective
  anti-emetic
• may be temporary measure
• vents fluid load proximal to obstruction,
  reducing vomiting stimulus
• often settles nausea
• NG fluid replacement (IV) not necessary
• oral fluids not precluded by NG at EOL

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Steroids (Benefits)

• reduce peri-tumoural edema
• potential benefit in metastatic disease involving
  both solid hollow viscus
• benefit usually seen in first 5 days in steroid
  naïve patients, if not then DC
• dexamethasone (Decadron) 4-8mg OD sq
• useful anti-emetic analgesic adjuvant

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Steroids (Drawbacks)

• glycemic control in DM
• candidiasis (antifungal)
• gastritis (gastric protection)
• steroid myopathy
• psychostimulant
• osteoporosis AVN not a concern in patients
  _at_EOL

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Anticholinergics

• reduction of secretions peristalsis
• hyoscine butylbromide (Buscopan)
• 10-20mg q4h sq
• in contrast to hyoscine HBr (Scopolamine)
• 40 compound, does NOT cross BBB
• does NOT contribute to delirium
• no role as centrally-acting anti-emetic

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Octreotide (Sandostatin)

• somatostatin analogue
• role well established in UGI bleeding
• reduction of splanchnic circulation
• ? secretions ? potential benefit in bowel
  obstruction (secretions ?)

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Octreotide

• secretory diarrhea
• 100 200 mcg q8-12h sq
• infusion sc or iv
• more effective than hyoscine butylbromide in
  reducing secretions
• funding through Section 16 (PCFA)

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Bowel Obstruction

• if nausea persists, consider trial of appropriate
  anti-emetic
• Reference
• http//www.fraserhealth.ca/media/13FHSymptomGuidel
  inesMalignantBowelObstruction.pdf

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Ascites
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Ascites

• in setting of malignancy
• often presenting feature of ovarian cancer
• seen with colon, lymphoma, pancreas, gastric
  hepatic metastases
• eventually intra-abdominal pressure ?s
• often accompanied by dyspnea
• reduced gastric capacity
• potential cause of vomiting
• may benefit from paracentesis

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Ascites

• ? diuresis in advanced cancer
• diuresis WILL aggravate intravascular volume
  depletion
• hypoalbuminemia frequent (cancer cachexia)
• paracentesis limit to symptom relief
• aggressive paracentesis ? further intravascular
  volume depletion

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Paracentesis

• blind vs ultrasound mark-up
• community vs institution
• thoracentesis pre-pack
• 14 g angiocath
• xylocaine
• sterile technique (gloves skin prep)
• community supplies CCAC

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One final thought

• any drug active within CNS is highly lipid
  soluble requires protein carrier
• as albumin falls progressively, more free drug
  becomes available
• ? effect ? toxicity
• high incidence of delirium at EOL
• ? reduce drug dose to match albumin level