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Controlling Nausea and Vomiting in Palliative Care Patients


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									Nausea and Vomiting in
Palliative Care Patients
       Dr Nial McCarron
     ST5 Palliative Medicine
 Definitions and prevalence
 review mechanisms/physiology of nausea and
 review possible causes of nausea/vomiting in
 palliative patients
 understand rationale behind selecting specific
 develop a systematic approach to managing
 nausea and vomiting
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,
 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
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
    Contributes to fears about starvation, dehydration
    and disease progression

  Significantly affects quality of life, compliance
  with treatment and health care cost
                                   Arch Int Med. 1986;146(10):2021-2023
 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 2007;298(10):1196-1207
Treatment Approach
 Evaluate the most likely aetiology of the
 patient’s nausea and vomiting

 Use pathophysiology knowledge to determine
 the likely mechanism and involved receptors

 Choose appropriate therapy to target these
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?
Evaluation of Aetiology
 Complete medication history
   Chemotherapy, opioids, antidepressants and

 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
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
       Radiological investigations eg abdominal radiography to
        exclude constipation or intestinal obstruction,
        ultrasonography to detect ascites.
Common Causes in Cancer Patients
 Liver metastases
 Malignant bowel obstruction
 External compression of stomach or intestines
 by tumor
 Primary or metastatic brain or leptomeningeal
 Pain medications
 Table 1. Causes of nausea and vomiting in people
 receiving palliative cancer care

             Causes                           Mechanism leading to nausea and

Chemical     Drugs (e.g. opioids,             Chemicals stimulate receptors in the
             cytotoxics, antibiotics)         chemoreceptor trigger zone
             Metabolic (e.g. organ failure,   Chemotherapy causes vagal receptor
             hypercalcaemia)                  stimulation
             Toxins (e.g. food poisoning,
             ischaemic bowel)

G.I.         Drugs (e.g. nonsteroidal anti-   Mechanoreceptors in the gut stimulate the
             inflammatory drugs, iron         vagus nerve, which acts on the vomiting
             supplements, antibiotics,        centre
or           cytotoxics)
             Intestinal obstruction
             Liver metastases
             Retroperitoneal cancer
Gastric stasis           Drugs (e.g. anticholinergics,    Gastric receptors stimulate the
                         opioids,tricyclics)              vagus nerve, which acts on the
                         Ascites                          vomiting centre
                         Peptic ulcer
                         Gastritis (e.g. stress, drugs,
                         Autonomic failure

Increased intracranial   Intracranial tumour or           Cerebral histamine receptors
pressure                 bleeding                         may be stimulated
                         Cerebral oedema                  Meningeal mechanoreceptors
                         Meningeal tumour                 stimulate the vomiting centre
                         Skull metastases

Movement-associated      Opioids                          Opioids induce sensitivity of
                         Gut distortion                   vestibular nerves
                         Gastroparesis                    Gut mechanoreceptors
                                                          stimulate the vagus nerve,
                                                          which acts on the vomiting

Anxiety-related          AnxietyAnticipatory vomiting     Cerebral cortex and vomiting
                         (e.g. before cytotoxic drugs)    centre
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

   Slowing of intestinal peristalsis
   Increased abdominal pressure and distention of bowel
   Activation of gut neurotransmitters
                                         ANJ. 2004;104(11):40-48
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. 2004;104(11):40-48
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
   Exacerbated by impaired hepatic metabolism and
   renal excretion in patients with end-stage cancer?

                                           ANJ. 2004;104(11):40-48
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
 [Thompson, 2004; Cancer Care Ontario, 2005; Perdue,
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
   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
   Make sure meals are small and palatable.
   Carbohydrate meals are often better tolerated.
   Offer cool, fizzy drinks (citrus flavours are often preferred).
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.
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).
 “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 2007;298(10):1196-1207
Classes of Antiemetic Agents
 Serotonin Antagonists
 NK1 Receptor Antagonist (i.e. Aprepitant)
 Dopamine antagonists
   Phenothiazines (i.e. Prochloroperazine)
   Butyrophenones (i.e. Haloperidol)
 Cannabinoids (i.e. Marinol®)
 Antihistiminic (H1) anti-muscarinic:
 Acts on receptors in the vestibular and vomiting centres
 NB anticholinergic effect on the bowel
 Onset of action: < 2 hours
 Duration of action: 4-6 hours
 Plasma halflife: 5 hours
 Adverse effects:
 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
 in bowel obstruction, raised intracranial pressure and
 movement induced nausea and vomiting.
Serotonin Antagonists
Ondansetron, Granisetron, Dolasetron, Palonosetron

                 Patient receives chemotherapy

           Enterochromaffin cells in GI tract are directly
                stimulated and release serotonin

                     Serotonin binds to 5HT3
                     vagal afferent receptors

                     Stimulation of Vomiting
                        Center in medulla
Serotonin Antagonists
Ondansetron, 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
 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
NK1 Receptor Pathway
                  Substance P

            Activates NK1 receptor

           Inositol phosphate signal
        transduction pathway activated

       Vomiting mediated through NTS and
             other parts of the cortex
NK1 Receptor Antagonist
Aprepitant (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
NK1 Receptor Antagonist
Aprepitant (Emend®)

    “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
 Mechanism of action:
 Dopamine antagonist (D2)
 5HT4 agonist (most important activity)
 5HT3 antagonist (>100mg/24 hrs)
 Place in Therapy
     Opioid-induced nausea and vomiting
     Malignant bowel obstruction (if incomplete)
     Impaired GI motility
 Adverse effects
 Acute dystonic reactions and oculogyric crisis
 Neuroleptic malignant syndrome
Phenothiazine Dopamine Antagonists
Levomepromazine (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 N&V
  Adverse effects
     Sedation (tx: decrease dose)
     Extrapyramidal effects (tx: diphenhydramine)
     Akathysia (tx: benzodiazepine)
Other Dopamine Antagonists
Haloperidol 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
 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
 Unknown mechanism of action
   Believed to act on CTZ and NTS, possible substance P

 Effective predominantly as an adjunctive agent

   Marinol: 5 – 10mg/m2 po q 3 - 4 hr
   CIII controlled substance

 Adverse effects
   Sedation, dizziness, hypotension, dysphoria
 Seen in up to 40% of patients receiving opioids
   Often resolves after 3-5 days of repeat dosing

   Decrease GI peristalsis via gut opioid receptors
   Activation of CTZ by central dopamine type 2

 Drugs of choice: Dopamine antagonists
Chemotherapy induced (CINV)

        American Society of Clinical Oncology 2006 (J Clin Oncol. 2006;24:2932-2947)
2006 ASCO Recommendations for Specific Emetic Risk
  Categories: Chemotherapy-Induced Acute Emesis

       High                    Moderate                    Low                            Minimal
     (>90%)                  (30% to 90%)              (10% to 30%)                       (<10%)
o Carmustine             o Carboplatin                o 5-Fluorouracil            o2-Chlorodeoxyadenosine
o Cisplatin              o Cyclophosphamide<1         o Bortezomib                oBevacizumab
o Cyclophosphamide         500 mg/m2                  o Cetuzimab                 oBleomycin
  ≥1500 mg/m2            o Cytarabine > 1             o Cytarabine ≤ 1000         oBusulfan
o Dacarbazine              gm/m2                        mg/m2                     oFludarabine
o Dactinomycin           o Daunorubicin               o Docetaxel                 oRituximab
o Mechlorethamine        o Doxorubicin                o Etoposide                 oVinblastine
o Streptozotocin         o Epirubicin                 o Gemcitabine               oVincristine
                         o Idarubicin                 o Methotrexate              oVinorelbine
                         o Ifosfamide                 o Mitomycin
                         o Irinotecan                 o Mitoxantrone
                         o Oxaliplatin                o Paclitaxel
                                                      o Pemetrexed
                                                      o Topotecan
                                                      o Trastuzumab

            Source: ASCO (American Society of Clinical Oncology Version 5/22/06

                             American Society of Clinical Oncology 2006 (J Clin Oncol. 2006;24:2932-2947)
Malignant Bowel Obstruction
   Peripheral pathways are stimulated
   CTZ is activated by inflammatory mediators and bacterial toxins

 Therapy of choice
   Surgery only recommended if life expectancy is > 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
Intractable Nausea/Vomiting
   Sometimes what we think should works, doesn’t
   Different in every patient

 Drugs of choice
   Combination therapy targeting different receptors
   Dosing of drugs around the clock (ATC), not prn
   Mirtazepine, cannabinoids, olanzapine
   Use of oral disintegrating tablets (ondansetron),
   intravenous or rectal formulations may be required
   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

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