1. Managing Gastro-intestinal symptoms
Dr Hattie Roebuck,
Consultant in Palliative Medicine
E mail:
Dec 2016

2. Assessing constipation – what does the pt mean?

3. Laxatives, PR intervention (BNF classification)
Stimulant
Softener
Senna
Picosulphate
Bisaccodyl
Glycerine supps
Na docusate at dose 200mg tds or less
Laxido/ movicol
Lactulose
Mg salts
Arachis oil enema
Phosphate enemas

4. Other options: Relistor
Indications: opioid induced constipation in terminally ill patients who have failed to respond to other laxatives
Methylnaltrexone -dose dependent on weight
Most pts 8 or 12mg s/c 2 doses 24hrs apart
Does not cross Blood brain barrier so analgesic effect of opioids unaffected
Cautions: faecal impaction, diverticular dx, colostomy, peritoneal catheter, liver or renal impairment
C/I: bowel obstruction, perforation
£21 per vial

5. Nausea vs Vomiting
Vomiting post chemo is much better controlled than nausea
Molassiotis A et al, Support Care Cancer 2008; 16: 201-8
The evidence for use of anti-emetics is poor
‘A systematic review of the treatment of nausea and/ or vomiting in cancer unrelated to chemotherapy or radiation’
M Davis. JPSM April 2010, Vol 39, no 4, p756

6. Common causes of N&V in advanced cancer
Drugs
Gastric stasis
Biochemical
Intestinal obstruction
Other
ICP
Lichter, 1993

7. Intractable nausea and vomiting
Definition:
“Nausea and vomiting that is not adequately controlled after multiple anti-emetics are used in series and/or in combination”
Those with the most difficult N&V to manage tend to be those with altered anatomy
eg due to malignant bowel obstruction (dysfunction) or stents/surgical interventions

8. A general approach - 1 Principles:8
A general approach - 1
Principles:
1) Initially - identify and treat reversible causes
This may not be appropriate if someone is imminently dying
2) Assess severity – does the patient need rehydration
3) Start anti-emetic treatment
Prescribe regularly
Review control every hours
A second line anti-emetic is required in 1/3 of patients

9. A general approach - 2 4) Consider route of administration9
A general approach - 2
4) Consider route of administration
Oral route maybe ineffective as frequent vomiting = poor absorption
Usually -> Syringe driver
Community options:
Rectal route: domperidone supps (true/false?)
Buccal prochlorperazine
Hysoscine patch
(granisetron patch)
Olanzapine orodispersible melt = 5mg strength

10. A general approach - 3 Remember N&V is often multi-factorial10
A general approach - 3
Remember N&V is often multi-factorial
Aim for acceptable control < 3 days
Consider whether dietary/ other factors may help.
Avoiding triggers
Parenteral fluids
Limiting oral intake, protein meals, low fat diet
Relaxation techniques
Acupuncture point P6
Ginger
Surgery (stents, venting g-tubes),

11. PHYSIOLOGY

12. Stomach – usually has slow wave contractions (3/min)
Rate increases with ‘circular vection’
Vasopressin release
Nausea perception related to vasopressin release
Primates – VP antagonists stop motion sickness
Humans – ginger reduces nausea, vp rise, reduced tachygastria in motion sickness trials

13. Dietary management
Protein meal – regulates gastrin release, which reduces gastric dysrhythmia & nausea
Gastroparesis diet:
Low fat – fat activates stretch receptors in stomach
Fluids
Maintains nutrition & hydration

15. Nucleus Tractus Solitarius Brainstem
Fear/Anxiety/
Memory;
Meningeal irritation;
Raised ICP
Drugs;
Metabolic products;
Bacterial toxins
CSF /
blood
Area Postrema Base 4th ventricle
CTZ
Cerebral cortex
Nucleus Tractus Solitarius Brainstem
Vomiting Centre
VIII nucleus
Peripheral pathways (outside of the CNS)
Motion;
Labyrinth disorders
Autonomic afferents
Emesis
Mechanical stretch (bowel obstruction or stasis); GI mucosal injury eg RT, chemo; local toxins; drugs

16. Metoclopramide Prokinetic
Dopamine 2 antagonist, 5HT4 agonist, 5HT3 antagonist
Central (CTZ) and peripheral action (gut mucosa)
Prokinetic effect antagonised by anticholinergic drugs
Side effects
Extrapyramidal symptoms
Drowsiness, restlessness, depression, diarrhoea
(Max 30mg in 24 hours for up to 5 days – EU review 2013)

17. Domperidone Side effects Prokinetic Dopamine 2 antagonist
Acts peripherally and at the CTZ
Does not readily cross the blood brain barrier
Oral only
Side effects
Rarely extrapyramidal
Hyperprolactinaemia
Cardiac arrhythmias
Max dose 10mg TDS (for up to 7 days)

18. Haloperidol Dopamine 2 antagonist, 5HT2a and α1antagonist
Acts predominantly at the CTZ but also peripherally (gut mucosa)
First line for biochemical induced N&V
T½ 13 – 35 hours
Side effects
Extrapyramidal, hyperprolactinaemia
Minimal sedation and hypotension
NB - Prolongation of QT interval

19. Cyclizine H1 antagonist and cholinergic muscarinic antagonist
Acts at the vestibular apparatus (& vomiting centre)
Plasma T½ 13 hours
Side effects
Drowsiness, urinary retention, dry mouth, blurred vision, constipation, headache, psychomotor impairment
Caution in severe liver disease, severe heart failure, renal failure, glaucoma

20. Cyclizine Not advocated for use in heart failure
Increases systemic & pulmonary arterial pressures
Increases right & left ventricular filling pressures
Counteract beneficial haemodynamic effects of opioids in heart failure
‘Detrimental haemodynamic effects of cyclizine in heart failure’ LB Tan
The Lancet March 1988

21. Hyoscine Hydrobromide / Butylbromide
Hyoscine butylbromide
Tertiary amine
Central AChm antagonist
anti-emetic
anti-secretory (d of a 1–9 hrs)
anti-spasmodic
Side effects
Drowsiness, agitation, delirium, bradycardia
Quaternary ammonium deriv
Peripheral AChm antagonist
anti-secretory (d of a < 2 hrs)
anti-spasmodic
Side effects
Dry mouth, blurred vision, constipation, urinary retention

22. Ondansetron 5HT3 antagonist Acts at CTZ and gut mucosa
Blocks amplifying effect of excess 5HT on vagus
Bowel wall enterochromaffin cells release 5HT by various stimuli. >Sensitises the vagal afferent nerves to emetogenic substances via 5HT3 receptors
Early N&V post chemo: First 24hrs after chemo only
Useful where excessive 5HT released eg chemotherapy or radiotherapy induced damage of gut mucosa, bowel distension, renal failure
Side effects
Headache, flushing, constipation

23. Aprepitant Neurokinin-1 receptor antagonist (NK1)
Substance P found widely in the CNS, including CTZ, VC and GI tract
Chemotherapy increases substance P levels as well as serotonin release
Antiemetic effects of NK1 antagonism is a central effect
Effective for delayed Chemo Induced N&V (>24hrs)
Given alongside 5HT3 antagonist and Dexamethasone
No evidence that it has much role in Palliative Care

24. Levomepromazine
Dopamine 2 antagonist, Muscarinic cholinergic antagonist, Histamine 1 antagonist, 5HT2A antagonist, alpha-adrenergic antagonist
Acts at vomiting centre
Plasma T½ 15 – 30 hours
Side effects
Sedation, weakness
Dry mouth, hypotension, extrapyramidal symptoms

25. Drugs and Receptors ++ + +++ Metoclopramide Domperidone Haloperidol
D2 antagonist
H1 antagonist
AChm antagonist
5HT2 antagonist
5HT3 antagonist
5HT4 agonist
Metoclopramide ++ +
Domperidone
Haloperidol
+++
Cyclizine
Hyoscine hydrobromide
Ondansetron
Levomepromazine
Olanzapine

26. Olanzapine Atypical antipsychotic Dopamine 1, 2, 3 and 4 antagonist
5HT2A, 5HT2C, 5HT3 and 5HT6 antagonist, Alpha-adrenergic antagonist, Histamine-1 antagonist, Muscarinic cholinergic antagonist
Acts at the Vomiting Centre
T½ 34 hours (↑ 52 hours in the elderly)
Side effects
Drowsiness, weight gain
Dry mouth, constipation, hypotension, peripheral oedema
Less movement disorders than with Haloperidol

27. Vomiting Centre 5HT3 NK1 CSF CTZ D2 Cerebral cortex H1 H1 VIII nucleus
AChm
AChm
Autonomic afferents
Emesis

28. Increases ACh production
5HT4
Gastrointestinal
Tract D2
5HT3

29. Dexamethasone Glucocorticoid
Reduces permeability of the CTZ and the blood brain barrier to emetogenic substances
Reduces neuronal content of GABA in the brain stem
Suggested that antagonism of PGs, release of endorphins and depletion of tryptophan may play a role
? central or peripheral effect

30. Summary Vomiting is unpleasant and debilitating
There are multiple causes
General measures and drug interventions are usually successful
It is helpful to understand the receptor basis of rational prescribing
But we cannot always control all associated symptoms

31. Medical management of bowel obstruction
Features of bowel obstruction:
Causes of bowel obstruction:
Intraluminal
Extraluminal
Motility disorders (tumour infiltration, neuropathic damage to GIT, drugs such as opioids, anticholinergics etc)
Constipation/ faecal impaction

32. Systematic review of surgery for malignant bowel obstruction (D
Systematic review of surgery for malignant bowel obstruction (D. Feuer et al, Gynaecological Oncology 1999)
Control of symptoms 42-80%
Re-obstruction rates 10-50% (most studies did not describe time scales)
Wide range of post op morbidity & mortality
Gynaecological Oncology 2003 Pothuri et al:palliative bowel obstruction in ovarian ca
Major surgical mobidity 22% - fistula/ abscess/ PE/ peritonitis/ sepsis
Perioperative mortality 6%
But survival mean 12months if palliation successful cf 3 months no surgery

33. How best to manage? 1.Surgical opinion & document time for audit
Non surgical: colic/ high risk perforation or no colic
2. Antiemetic: Stimulant antiemetic/ Non stimulant
3. Laxative (non stimulant)
4. Steroid s/c or IV (NNT 6)
5. NG/ antisecretory
6. Fluids?

34. Subacute bowel obstruction can resolve
Prognosticating hard
Outcomes:
Subacute bowel obstruction can resolve
Most pts will have a recurrence unless have treatment options such as chemotherapy still available to them
Pts can live with subacute bowel obstruction for some months, equates to gut failure
Psycho-social impact can be profound; inability to eat
US – use of parenteral nutrition>UK
Risk of death, sudden deterioration if perforate
Sudden increased pain

35. Summary
Effect on GIT helpful in determining which laxatives and anti-emetics to use
Adherence to laxative regime can be challenging
Nausea & Vomiting evidence base is poor
Rational prescribing makes sense
Bowel obstruction has significant complications, including death or for chronic subacute bowel obstruction, psycho-social. Equates to gut failure.

36. Further reading
‘Treating nausea & vomiting in palliative care: a review’ P Glare.
Clinical Interventions in Aging 2011; 6 p243
Wood G et al. Management of Intractable Nausea and Vomiting in Patients at the End of Life: “I Was Feeling Nauseous All of the Time…Nothing Was Working” in McPhee S et al (eds) Care at the Close of Life: Evidence and Experience, 2010