Sam H Ahmedzai Academic Unit of Supportive Care Department of Oncology The University of Sheffield & Sheffield Teaching Hospitals NHS Foundation

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1 Sam H Ahmedzai Academic Unit of Supportive Care Department of Oncology The University of Sheffield & Sheffield Teaching Hospitals NHS Foundation Trust

2 Overview Which drugs? How much? How to give? Adverse effects (Oxygen and airflow will not be covered)

3 Don t forget value of anti-cancer treatments for palliating dyspnoea 1. Radiotherapy Cachia, Ahmedzai Eur J Cancer 2008

4 Don t forget value of anti-cancer treatments for palliating dyspnoea 2. Chemotherapy Cachia, Ahmedzai Eur J Cancer 2008

5 Supp Care Cancer 2008 Opioids Benzodiazepines Phenothazines

6 Actions of drugs on dyspnoea Cachia, Ahmedzai Eur J Cancer 2008 Drug class Pharmacological action Opioid Benzodiazepine Relieves dyspnoea at cerebral level? Reduces ventilatory response to hypercapnia Reduces anxiety Causes sedation Relieves pain? Reduces cough Reduces cardiac pre-load Reduces cardiac after-load Reduces afferent signalling from lungs?

7 Opioids for palliation of dyspnoea Where do opioids act to reduce sensation? Depression of medullary chemoreceptors may not be relevant (Muers, 2002) PET and fmri evidence of dyspnoea activation of anterior cingulate gyrus, insula, amygdala similar areas for pain, thirst, hunger (Liotti et al, 2000) Possibility that opioid receptors in these areas can modulate sensation and affective response to dyspnea - without involving respiratory drive

8 Benefits of opioids in dyspnea Relief of dyspnoea Improved exercise tolerance Relief of cough Relief of chest pain Sedation / reduction in anxiety Cardiovascular relief in left ventricular failure

9 Actions of opioids in dyspnoea Drug Codeine Dihydrocodeine What does it do? No benefit Effective - but weak and side-effects Morphine COPD Cancer Exercise tolerance Conflicting evidence on dyspnoea Effective

10 11 patients admitted to palliative care unit Non-randomised, uncontrolled study Detailed comparison of effects of nasal oxygen with morphine Series of studies by this group and others Show that opioids rapidly reduce ventilation (respiratory rate) But tidal volume can go up so minute ventilation (SaO 2 ) remains steady (at first)

11 Significant reduction of dyspnoea after morphine but not oxygen

12 Respiratory rate decreased significantly with morphine but no other evidence of respiratory depression

13 Significant reduction of ANXIETY with morphine was this the main effect?

14 BMJ 2003 Double blind RCT Slow release morphine 20mg daily versus placebo + Docusate + Senna Improvement in dyspnoea scores (but clinically significant?) Major problem with constipation

15 BMJ 2003

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17 Which opioid to use for dyspnoea? No head to head comparisons! Reasons to avoid morphine Higher rates of constipation, nausea, sedation cf fentanyl (Ahmedzai 1997; Clark 2004) Higher rate of cognitive effects cf oxycodone (Mucci-LoRusso 1998) Morphine releases histamine and tryptase via mast cell degranulation not by fentanyl or buprenorphine (non-opioid effect Blunk 2004) Buprenorphine has least respiratory depressant effect of all current opioids

18 JPSM 2013

19 What about buprenorphine? Complex activity at opioid receptors Partial agonist at mu Antagonist at kappa Agonist at ORL-1 Largely ignored by palliative medicine because of lack of understanding of actions emetic side-effects with immediate release oral preparation New sustained release patch

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23 Benzodiazepines for dyspnoea Evidence for relief of anxiety and possibly dyspnoea in COPD Risk of sedation or benefit? Buspirone less respiratory depression, but slow onset Lorazepam better than diazepam - shorter half-life and cleaner metabolism Midazolam for rapid titration + syringe drive

24 Navigante et al, JPSM 2006

25 Navigante et al, JPSM 2006

26 Navigante et al, JPSM 2006

27 Navigante et al, JPSM 2006

28 JPSM 2012

29 What s new? Nebulised furosemide (20-40mg) Acts on airways mechanical receptors Modulates afferent neural pathways Reduces bronchospasm Variable results in dyspnoea Positive small uncontrolled series (Nishino et al, 2000) Positive study in volunters (Moosavi et al, 2006) Negative studies in palliative care (Stone, 2002; Wilcock 2008)

30 10 volunteers Enforced air hunger by restricted ventilation and induced hypercapnia Dyspnoea measured on 100mm VAS Nebulised 40mg furosemide vs placebo Air hunger reduced from 58 to 39 Allowing for placebo, effect was 13% of full scale (p=0.052) Subjects had diuresis

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32 No changes in respiratory parameters (PCO 2 or VE)

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36 Actions of drugs on dyspnoea Cachia, Ahmedzai Eur J Cancer 2008 Drug class Pharmacological action Relieves dyspnoea at cerebral level Reduces ventilatory response to hypercapnia Opioid Benzodiazepine Nebulised furosemide? Reduces anxiety Causes sedation Relieves pain? Reduces cough Reduces cardiac pre-load Reduces cardiac after-load? Reduces afferent signalling from lungs?

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38 What are the challenges?

39 JPSM 2012

40 J Pall Med 2012

41 J Pall Med 2012

42 J Pall Med 2012

43 J Pall Med 2012

44 What are the challenges? Which drugs especially opioids Which route How to titrate? Combinations of drugs Breakthrough dyspnea

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