NAUSEA!

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NAUSEA! Brought to you by...
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Management of Nausea in End-Stage Disease

• Creswick Autumn 2009

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Hey little cave kiddy, dont eat that berry or
youll die!

• Catherine Deveney
• The Age 15th April 2009

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Nausea and Vomiting (Emesis)

• Emesis is a reflex, developed to different
  degrees in different species, that allows an
  animal to rid itself of ingested toxins or
  poisons.

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Amanita phalloidesAmanitins block RNA
Transcription..
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Why Worry about Nausea?

• Frequency gt 50 of all cancer patients
• Causes severe distress to patient
• Multiple causes
• Radiation, chemotherapy, drugs, toxins,
  metabolic derangements, GI obstruction, anxiety
  and phobias, etc.
• Barnes M J Pain Sympt Manage 1988381-85

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End-of-life Nausea

• Cancer 6 to 68 of patients
• (19 studies, 9,140 patients)
• AIDS 43 to 49 of patients
• (2 studies, 689 patients)
• Heart Disease 17 to 48 of patients
• (3 studies, 146 patients)
• Renal Disease 30 to 43 of patients
• (3 studies, 362 patients)
• Solano JP, Gomes B, Higginson IJ. A comparison
  of symptom prevalence
• in far advanced cancer, AIDS, heart failure,
  chronic obstructive pulmonary
• disease, and renal disease. J Pain Symptom
  Manage. 2006315869.

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Compare.

• Thoughtful use of analgesics, with consideration
  of causation
• with
• Relatively thoughtless use of a small number of
  antiemetics

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Present approaches

• Ad hoc, thus perhaps ad nauseam rather than ad
  rem - to the point!
• Resource wasteful
• Cost, esp. of 5-HT3 antagonists
• Use of nursing time
• Ineffective
• E.g. 5-HT3 antagonists in opiate nausea
• And so contribute to ongoing suffering

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Apply a little Science..or, up the garden path to
the brainstem
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Plan for the Next 20 minutes!

• Examine receptors and pathways
• Examine the drugs we use
• Examine evidence for use of antiemetics in
  palliative care
• Examine our approach to the patient

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In the Brainstem
Fourth Ventricle
Vomiting Centre
Chemoreceptor Trigger Zone
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Vomiting Centre

• Diffuse network, central pattern generator
• Integrating multiple stimuli
• Parasympathetic and motor efferents result in
  vomiting
• Main Receptors
• Histamine (H1)
• Muscarinic cholinergic (Achm)
• Serotonin type 3 5-HT3
• Serotonin type 2 (5-HT2)
• Tachykinin NK1 (for Substance P)

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Inputs to the Vomiting Centre
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Chemoreceptor Trigger Zone

• Monitors blood chemistry
• Floor of fourth ventricle
• No blood-brain barrier
• CSF capillaries in close contact
• Pathways to Vomiting Centre
• Main Receptors
• Dopamine (D2) and Serotonin Type 3 (5-HT3)

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Drug categories and examples

• Butyrophenones - haloperidol
• Prokinetic agents - metoclopramide
• Phenothiazines - prochloperazine
• Antihistamine ACh - cyclizine
• Anticholinergic - hyoscine
• 5-HT3 antagonists ondansetron
• NK1 Receptor (Substance P) antagonist - aprepitant

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Haloperidol

• Butyrophenone antipsychotic
• D2 receptor antagonist
• Therefore effective at CTZ
• Therefore effective for circulating toxin
  (including drug) induced nausea, e.g.
• Opioids, digoxin
• Hypercalcaemia, uraemia

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Metoclopramide

• Prokinetic anti-emetic
• D2 receptor antagonist
• 5HT4 receptor agonist
• (5HT4 receptor in gut stimulates peristalsis)
• In high doses Serotonin type 3 5-HT3
• Added clinical value prokinesis
• As a D2 antagonist 2nd to haloperidol
• As a 5HT3 antagonist 2nd to specifics

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Cyclizine

• Antihistamine (H1)
• Antimuscarinic (Achm)
• Action on vomiting centre
• Effective for
• Mechanical bowel obstruction
• Raised intracranial pressure
• Motion sickness

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USN Troopship General CC Ballou
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Levomepromazine

• NozinanR
• D2 receptor antagonist
• Alpha 1 adrenergic antagonist (?BP)
• 5HT2 antagonist
• Sedative, analgesic
• S100 availability

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Ondansetron

• Serotonin type 3 5-HT3 antagonist
• Developed specifically for control of emesis in
  chemotherapy
• Blocks the amplifying effect of excess serotonin
  (5HT) on vagal nerve fibres
• Useful
• Chemotherapy, radiotherapy, bowel distension,
  renal failure

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5HT3 Receptor antagonists

• Ondansetron
• Adverse effects
• Constipation
• Headache
• Flushing and hiccup

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Hardy D, Daly S, McQuade B, et alA double-blind
randomised, multinational, multicentre study
comparing a single dose of ondansetron 24mg p.o.
with placebo and metoclopramide 10mg t.d.s. p.o.
in the treatment of opioid induced nausea and
emesis in cancer patients.Supportive Care in
Cancer. 10(3)231-6, 2002 Apr

• 92 patients. No significant difference in the
  proportion of patients achieving complete control
  of emesis.

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Community Cost

• Ondansetron 8mg tabs 3 daily for one week 14
  each
• 294.00
• Metoclopramide tablets 10mg 3 daily for one week
  0.06 each
• 1.26
• .....and the placebo?

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Hyoscine

• Muscarinic cholinergic (Achm)
• Hyoscine hydrobromide
• Hyoscine butylbromide (BuscopanR)
• Indications
• Bowel obstruction
• Drooling
• Death rattle

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Aprepitant

• Tachykinin NK1 receptor antagonist
• (Substance P antagonist SPA)
• Treatment of delayed emesis in chemotherapy and
  post-operative nausea and vomiting
• Oral, once daily
• SIDE EFFECTS Tiredness, weakness, nausea,
  constipation, diarrhea, loss of appetite, upset
  stomach, dizziness, headache and hiccups.

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Cochrane Nausea in Palliative Care
First day effect
Not done yet
No Evidence
Both proposals only
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Caresearch Review Collection Nausea

• Glare P, Pereira G, Kristjanson LJ, Stockler M,
  Tattersall M.
• Systematic review of the efficacy of antiemetics
  in the treatment of nausea in patients with
  far-advanced cancer.
• Support Care Cancer 2004 Jun12(6)432-40
• Evidence supporting the existing consensus-based
  guidelines for management of nausea and vomiting
  in advanced cancer is sparse. Current approaches
  to treatment based on the neuropharmacology of
  the emetic pathway may be inappropriate in this
  setting. Well-designed studies of the impact of
  "standard" management and novel agents on nausea
  and vomiting in palliative populations are needed.

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• There is a large gap in the evidence base
  regarding high-quality studies in the management
  of nausea and vomiting in chronic advance disease
  other than related to cancer treatments. In order
  to optimize treatment and minimize side effects,
  the current management of nausea targets specific
  receptors, which vary by underlying
  pathophysiology.

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The Real World

• We need to be able to diagnose the common
  causes of nausea in end-stage disease, treat if
  possible, and in any case effectively administer
  the right anti-emetic, using knowledge of the
  pathways tempered by practicalities.

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Approaching the patient
Mind, Brain Blood Gut

• Mind
• Brain
• Blood
• Gut

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Approaching the patient
A Focussed History Examination

• Mind
• Brain
• Blood
• Gut

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Mind
Each time the wave breaks the raven Gives a
little jump

• Each time the wave breaks
• the raven
• Gives a little jump
• Nissha
• (Tr. R.H. Blyth,
• SenryuJapanese Satirical Verses)

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Mind looking for..

• Cognitive impairment
• Anxiety
• Depression
• Fear/Anticipation
• Response to pain
• .or is the patient just plain terrified?

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Brain looking for..

• Vestibular disease
• Raised intracranial pressure

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Blood looking for..

• A drug related cause
• Opioids cause nausea in more than 20..
• Dehydration
• Metabolic causes such as elevated Ca
• Renal failure
• Hepatic failure
• Infection

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Gut looking for

• Reflux
• Gastric distension
• Ascites
• Hepatomegaly
• Bowel obstruction
• Chemotherapy
• Radiotherapy
• Constipation

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Gut

• It is quite necessary to examine the mouth and
  to do a rectal examination in patients with
  nausea.

If you dont put your finger in, you put your
foot in it
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Gut
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Approach to Emesis

• Take a history, do a targeted examination. Treat
  the underlying cause if you can, and use your
  knowledge of the receptors and pathways to make a
  best initial choice of anti-emetic, delivering
  this drug in the most effective way.
• .sic ad nauseam

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