2. Find out more online: www.worcestershire.nhs.uk Opioids and anti-emetics in palliative care Dr Claire Curtis Consultant in Palliative Medicine

3. Find out more online: www.worcestershire.nhs.uk Summary ● Opioids ●Why not morphine? ●What other opioids are available? ●How to choose ● Anti-emetics ●What is there? ●How to choose

4. Find out more online: www.worcestershire.nhs.uk Morphine

5. Find out more online: www.worcestershire.nhs.uk Morphine ● Opioid of choice ● Given orally unless good reason why not ● Long acting form ●MST, Morphgesic, Zomorph ●Peak plasma conc 2-6h, lasts 12h ● Short acting form ●Oramorph, sevredol ●Peak plasma conc within 1 hr, lasts 4h ● Injectable form ● Acts on mainly mu opioid receptors

6. Find out more online: www.worcestershire.nhs.uk Morphine ● Metabolised in liver ● Well tolerated in mild/moderate hepatic failure, may need to reduce dose in severe hepatic failure ● Excreted by kidneys – so risk in renal impairment of accumulating metabolites and developing adverse effects ● No clinically relevant ceiling effect for analgesia ● Required doses vary between individuals

7. Find out more online: www.worcestershire.nhs.uk Opioid adverse effects ● Management strategy ●Dose reduction ●Therapy to treat adverse effect ●Opioid switching ●Adjuvant analgesics to reduce opioid requirement

8. Find out more online: www.worcestershire.nhs.uk Therapy for opioid AE ● N&V ●often self-limiting so may only need short course of anti-emetic ●Metoclopramide or haloperidol ● Constipation ●Combination of softener (docusate) plus stimulant (senna) ●Titrate up, and consider pr intervention ● Drowsiness ●Usually self-limiting ●Review other centrally acting drugs, correct metabolic disturbances, reduce dose, ?methylphenidate

9. Find out more online: www.worcestershire.nhs.uk Therapy for AE ● Delerium ●Treat contributory causes inc other drugs ●Reduce dose, haloperidol ● Xerostomia ●Mouth care, review drugs, artificial saliva, pilocarpine? ● Pruritus ●Ondansetron ● Sweating ●Antimuscarinic

10. Find out more online: www.worcestershire.nhs.uk Opioid toxicity ● Drowsiness, hallucinations, confusion, vomiting, myoclonus, pinpoint pupils, resp depression ● Precipitated by: ●Excessive increase in dose ●Use in opioid insensitive pain ●Dehydration or renal impairment ●Infection ●Other change in disease status – weight loss, hepatic function ●Reduction in analgesic requirements ●Drug interaction eg amitryptilline

11. Find out more online: www.worcestershire.nhs.uk Why not morphine? ● Intolerable undesirable side effects ● Other patient factors – preference, compliance, setting ● Renal impairment ● Route of administration ● Availability ● Therapeutic ●Inter-individual response varies from opioid to opioid, switching may produce better analgesia

12. Find out more online: www.worcestershire.nhs.uk Changing route of administration from oral ● Reduced conscious level ● Dysphagia ● Nausea/vomiting ● Malabsorption ● Tablet burden/compliance ● Sc/transdermal/intrathecal/epidural ● Not im – painful, reduced muscle mass

13. Find out more online: www.worcestershire.nhs.uk Before substituting ● Consider: ● Dose reduction ● Rehydration ● Adjuvant medications to improve undesirable side effects ●Anti-emetic, laxative, haloperidol for hallucinations ● Check for drug interactions ●Eg erythromicin and fentanyl

14. Find out more online: www.worcestershire.nhs.uk Dose? ● Equivalent dose conversions known ● Are only approximate ● Less precise as dose increases ● Consider: ●concurrent morbidity ●Renal impairment ●Hepatic impairment

15. Find out more online: www.worcestershire.nhs.uk Remember ● Rescue medication

16. Find out more online: www.worcestershire.nhs.uk Diamorphine

17. Find out more online: www.worcestershire.nhs.uk Diamorphine ● Parenteral route only ● Usually given continuously via syringe driver plus prn sc bolus doses ● Time to onset of action sc = 10-30 mins ● Duration of action = 3-4h

18. Find out more online: www.worcestershire.nhs.uk Diamorphine vs morphine sc ● Diamorphine more soluble = smaller volume = so in higher doses easier to fit in syringe driver ● Metabolised by liver to 6-mono-acetylmorphine which is metabolised to morphine ● Metabolism then as morphine – so metabolites accumulate in renal impairment ● Sc morphine = 2 x po morphine ● Sc diamorphine = 3 x po morphine

19. Find out more online: www.worcestershire.nhs.uk Oxycodone

20. Find out more online: www.worcestershire.nhs.uk Oxycodone ● Long acting form ●Oxycontin ●Peak plasma conc 3h, lasts 12h ● Short acting form ●Oxynorm capsules or solution 5mg/5ml or 10mg/ml ●Onset 20-30mins, lasts 4-6h ● Injectable form ● Acts mainly on mu opioid receptors ● Metabolised in liver ● 10 - 20% excreted unchanged by kidneys – can accumulate in RF

21. Find out more online: www.worcestershire.nhs.uk Oxycodone ● Potency ●oral oxycodone = 1.5 – 2 x oral morphine ●sc oxycodone = 1.5 – 2 x oral oxycodone ● Choice ●Intolerable undesirable side effects from morphine ●Therapeutic ●Inter-individual response varies from opioid to opioid, switching may produce better analgesia ●Anecdotal evidence can help if neuropathic element to pain

22. Find out more online: www.worcestershire.nhs.uk Transdermal fentanyl

23. Find out more online: www.worcestershire.nhs.uk Transdermal Fentanyl ● Fentanyl – mu opioid receptor agonist ● Lipophilic (unlike morphine) – more easily crosses BBB so different SE profile to morphine ●Less constipation ●Often less nausea/vomiting

24. Find out more online: www.worcestershire.nhs.uk Transdermal fentanyl ● Patch (cannot ensure interchangability) ●Matrix: Durogesic Dtrans, Matrifen ●Reservoir: Tilofyl ●12 – 100 mcg/hr ●Onset of analgesia = 3h ●Steady state reached 36-48h after patch applied (but can take up to 9-12 days) ie can’t be altered quickly ●Lasts 72h (small minority 48h)

25. Find out more online: www.worcestershire.nhs.uk Transdermal Fentanyl ● Metabolised in liver to inactive metabolite – safe in RF ● Potency ●TD fentanyl = 100 x oral morphine ●25 patch = 60-90mg oral morphine/24 hrs ●100 patch = 315 – 405mg oral morphine/24 hrs ● Rate increased if skin is warm

26. Find out more online: www.worcestershire.nhs.uk Why transdermal fentanyl? ● Intolerable undesirable side effects (esp constipation) ● Other patient factors – preference, compliance ● Renal impairment ● Route of administration – non-oral ● Therapeutic ●Inter-individual response varies from opioid to opioid, switching may produce better analgesia ● NOT if rapidly changing pain (can take >2 days to reach maximum analgesic effect)

27. Find out more online: www.worcestershire.nhs.uk Alfentanil

28. Find out more online: www.worcestershire.nhs.uk Alfentanil ● Parenteral only (500mcg/ml) ● Synthetic derivative of fentanyl ●More rapid onset <5min ●shorter duration 30-60 mins, ●less potent (1/4) ●available in more concentrated form – so used in preference to sc fentanyl ● Like fentanyl – safe in renal failure ●Analgesic of choice for renal LCP

29. Find out more online: www.worcestershire.nhs.uk Alfentanil ● Potency ●Sc alfentanil = 30-40 x oral morphine/24hrs ●2mg alfentanil/24hrs = 60mg oral morphine/24hrs ●Sc prn doses 1/6 24hr anfentanil dose (but may use sc oxycodone as duration of action longer) ● Choice ●Renal failure where patient EOL or has rapidly changing pain so that transdermal fentanyl not suitable

30. Find out more online: www.worcestershire.nhs.uk Buprenorphine

31. Find out more online: www.worcestershire.nhs.uk Transdermal Buprenorphine ● Partial μ-opioid receptor and opioid-receptor-like (ORL- 1) agonist and a gamma and kappa opioid receptor antagonist ● Highly lipid soluble ● Strong receptor affinity – need bigger doses of naloxone to reverse effect

32. Find out more online: www.worcestershire.nhs.uk Transdermal Buprenorphine ● Matrix Patches ●Butrans ●Changed every 7 days: 5,10,20 mcg/hr ●Time to peak plasma con = 3 days ●Transtec ●Changed every 4 days: 35, 52.5, 70 mcg/hr ●Time to peak plasma conc = 60h

33. Find out more online: www.worcestershire.nhs.uk Transdermal Buprenorphine ● Metabolised in liver and bowel wall to active metabolites which don’t cross BBB ● Mainly excreted in faeces – so safe in renal impairment ● Potency ●TD buprenorphine = 100 x oral morphine ●5 mcg patch = 12 mg oral morphine/24hrs ●70mcg patch = approx 200mg oral morphine/24hrs ●ie equipotent to fentanyl but biggest patch size = 70

34. Find out more online: www.worcestershire.nhs.uk Why Transdermal buprenorphine? ● As for fentanyl ●SE (esp constipation)Patient factors – preference, compliance ●Renal impairmentRoute of administration – non-oral ●Therapeutic ●Inter-individual response varies from opioid to opioid, switching may produce better analgesia ● NOT if rapidly changing pain (can take >2 days to reach maximum analgesic effect) ● Harder to reverse than fentanyl in overdose ● Can start at much lower opioid dose

35. Find out more online: www.worcestershire.nhs.uk Hydromorphone

36. Find out more online: www.worcestershire.nhs.uk Hydromorphone ● Mu opiod receptor agonist ● Metabolised in liver, excreted in kidneys ● Long acting form ● Short acting form, inc buccal ● Sc form ● ?safer than morphine in renal impairment ● 7.5 x more potent than morphine ● 2mg hydromorphone po = 15mg morphine po

37. Find out more online: www.worcestershire.nhs.uk Transmucosal fentanyl

38. Find out more online: www.worcestershire.nhs.uk Transmucosal fentanyl ● Buccal ●Actiq, Abstral, Effentora ● Nasal ●Instanyl, sublimaze ● SPC prescription only (except Actiq) ● Rapid onset analgesia

39. Find out more online: www.worcestershire.nhs.uk Nausea and Vomiting

40. Find out more online: www.worcestershire.nhs.uk Nausea and vomiting ● Nausea often more distressing than vomiting ● Need to distinguish between vomiting, expectoration and regurgitation ● When choosing anti-emetic need to consider cause of the symptoms and treat the reversible

41. Find out more online: www.worcestershire.nhs.uk Causes of nausea and vomiting in advanced cancer ● Gastrointestinal ●Gastric stasis, obstruction ● Drugs ●Opioids, antibiotics, NSAIDS, iron ● Metabolic ●Hypercalcaemia, renal failure ● Toxic ●RT, chemo, infection, paraneoplastic ● Brain mets ● Psychosomatic ● Pain

42. CHEMORECEPTOR TRIGGER ZONE VESTIBULAR APPARATUS CEREBRAL CORTEX VAGUS & SPLANCHNIC NERVES VOMITING CENTRE Drugs Metabolic Pharyngeal irritation Gastric stasis Gastro-intestinal distension Fear Pain Motion sickness Cerebral tumours 5HT 2 µ NK 1 H 1 ACh M D 2 5HT 3 D 2 5HT 4 5HT 3 BLOOD BRAIN BARRIER Neuropharmacology GI TRACT

43. Find out more online: www.worcestershire.nhs.uk Non-drug methods ● Avoid precipitants ●Malodour ●Certain foods ● Small snacks not large meals ● Accupressure wrist bands ● Hypnotherapy, accupuncture etc

44. Find out more online: www.worcestershire.nhs.uk Drugs ● Single anti-emetic initially ● May be necessary to combine drugs ●Eg if different causes for the nausea/vomiting ● May be possible to use oral route ● Persistent vomiting will require non-oral route – commonly sc via syringe driver

45. Find out more online: www.worcestershire.nhs.uk Metoclopramide

46. CHEMORECEPTOR TRIGGER ZONE VESTIBULAR APPARATUS CEREBRAL CORTEX VAGUS & SPLANCHNIC NERVES VOMITING CENTRE Drugs Metabolic Pharyngeal irritation Gastric stasis Gastro-intestinal distension Fear Pain Motion sickness Cerebral tumours 5HT 2 µ NK 1 H 1 ACh M D 2 5HT 3 D 2 5HT 4 5HT 3 BLOOD BRAIN BARRIER Metoclopramide GI TRACT Metoclopramide

47. Find out more online: www.worcestershire.nhs.uk Metoclopramide ● Use ●GI stasis, Drug induced ● SE: include extra-pyramidal symptoms ● Oral dose ●Up to 20mg tds ● Sc dose ●10mg prn, max 2hrly ●30-100mg/ 24hrs

48. Find out more online: www.worcestershire.nhs.uk Domperidone ● D2 antagonist as metoclopramide ● Does not cross BBB ● May be better tolerated than metoclopramide ● No parenteral formulation ● Oral dose up to 20mg qds

49. Find out more online: www.worcestershire.nhs.uk Cyclizine

50. CHEMORECEPTOR TRIGGER ZONE VESTIBULAR APPARATUS CEREBRAL CORTEX VAGUS & SPLANCHNIC NERVES VOMITING CENTRE Drugs Metabolic Pharyngeal irritation Gastric stasis Gastro-intestinal distension Fear Pain Motion sickness Cerebral tumours 5HT 2 µ NK 1 H 1 ACh M D 2 5HT 3 D 2 5HT 4 5HT 3 BLOOD BRAIN BARRIER Cyclizine GI TRACT Cyclizine

51. Find out more online: www.worcestershire.nhs.uk Cyclizine ● Use: drug induced, metabolic, central cause ● SE: confusion ● Oral dose ●Up to 50mg tds ● Sc dose ●50mg prn max 2 hrly ●50-150mg/24hrs

52. Find out more online: www.worcestershire.nhs.uk Haloperidol

53. CHEMORECEPTOR TRIGGER ZONE VESTIBULAR APPARATUS CEREBRAL CORTEX VAGUS & SPLANCHNIC NERVES VOMITING CENTRE Drugs Metabolic Pharyngeal irritation Gastric stasis Gastro-intestinal distension Fear Pain Motion sickness Cerebral tumours 5HT 2 µ NK 1 H 1 ACh M D 2 5HT 3 D 2 5HT 4 5HT 3 BLOOD BRAIN BARRIER Haloperidol GI TRACT Haloperidol

54. Find out more online: www.worcestershire.nhs.uk Haloperidol ● SE: include extrapyramidal effects, sedation ● Use – drug induced/metabolic cause ● Oral dose ●Start 1.5-3mg nocte, may be up to 5mg bd ● Sc dose ●1-2.5mg prn max 2 hrly ●2.5-10mg /24 hrs

55. Find out more online: www.worcestershire.nhs.uk Levomepromazine

56. CHEMORECEPTOR TRIGGER ZONE VESTIBULAR APPARATUS CEREBRAL CORTEX VAGUS & SPLANCHNIC NERVES VOMITING CENTRE Drugs Metabolic Pharyngeal irritation Gastric stasis Gastro-intestinal distension Fear Pain Motion sickness Cerebral tumours 5HT 2 µ NK 1 H 1 ACh M D 2 5HT 3 D 2 5HT 4 5HT 3 BLOOD BRAIN BARRIER Levomepromazine GI TRACT Levomepromazine

57. Find out more online: www.worcestershire.nhs.uk Levomepromazine ● Broad spectrum – single anti-emetic if multiple causes ● SE: sedation ● Oral dose ●6 – 12.5mg nocte ● Sc dose ●5mg prn max 2 hrly ●5-25mg/24hrs (larger doses cause sedation and probable no additional anti-emetic effect)

58. Find out more online: www.worcestershire.nhs.uk Ondansetron

59. CHEMORECEPTOR TRIGGER ZONE VESTIBULAR APPARATUS CEREBRAL CORTEX VAGUS & SPLANCHNIC NERVES VOMITING CENTRE Drugs Metabolic Pharyngeal irritation Gastric stasis Gastro-intestinal distension Fear Pain Motion sickness Cerebral tumours 5HT 2 µ NK 1 H 1 ACh M D 2 5HT 3 D 2 5HT 4 5HT 3 BLOOD BRAIN BARRIER Ondansetron GI TRACT Ondansetron

60. Find out more online: www.worcestershire.nhs.uk Ondansetron ● Use – N&V ass with serotonin release ●Chemo, RT, bowel injury ● SE: constipation, prolongs QT interval ● Oral Dose: 4-8mg max tds ● Sc dose ●4 – 8 mg prn max tds ●8-16mg / 24 hrs(occ up to 32mg)

61. Find out more online: www.worcestershire.nhs.uk Other anti-emetics ● Prochlorperazine ●As levomepromazine but greater risk of extrapyramidal SE, fewer antimuscarinic effects and less sedation ●Buccal formulation ● Dexamethasone ●Many uses ● Hyoscine hydrobromide ● Hyoscine butylbromide

62. Find out more online: www.worcestershire.nhs.uk Anticipatory prescribing ● Should be done for all patients who are on the practice’s palliative care register who are expected to have only weeks to live ● May be done for patients who have an expected longer prognosis ● To plan for when subcutaneous medication needed at short notice eg OOH

63. Find out more online: www.worcestershire.nhs.uk Anticipatory prescribing: What? ● Analgesic ● Anti-emetic ● Anti-secretory ● Anxiolytic ● Drugs then kept in the house in a “just in case” box

64. Find out more online: www.worcestershire.nhs.uk “Just in case” boxes ● A plastic box kept in the patient’s home ● Keep all anticipatory medication and associated kit ● Doesn’t contain a syringe driver ● Labelled ● Kept in safe place – may be there weeks ● Patient info leaflet

65. Find out more online: www.worcestershire.nhs.uk Anticipatory Prescribing: How? ● Drugs may have been dispensed and be in the house ● Need to be written on a syringe driver prescription chart in order for DNs to administer them ● Graseby syringe drivers being replaced with McKinley syringe pumps ● Drug charts reviewed and changed

66. Find out more online: www.worcestershire.nhs.uk

67. Find out more online: www.worcestershire.nhs.uk

68. Find out more online: www.worcestershire.nhs.uk

69. Find out more online: www.worcestershire.nhs.uk Summary

70. Find out more online: www.worcestershire.nhs.uk Choice of opioids ● Oral morphine unless good reason not ● Other opioids available. Consider: ●Mode of delivery ●Side effects ●Renal impairment

71. Find out more online: www.worcestershire.nhs.uk Choice of anti-emetic ● Consider cause ● Ensure regular, maximal dose ● May need to combine anti-emetics ● Consider sc route

72. Find out more online: www.worcestershire.nhs.uk References/useful resources ● West Midlands Palliative Care Physicians: Guidelines for the use of drugs in symptom control. Jan 2007. ● Palliative Care Guidelines Plus ●http://book.pallcare.info/index.phphttp://book.pallcare.info/index.php ● www.palliative drugs.com www.palliative ● Palliative care formulary. 3 rd Ed. Twycross, Wilcock