Key points This presentation is in line with the goals of the Fundamentals programme – complex symptom management and prescribing has not been addressed – consider a masterclass for this. We acknowledge there may be local variance in prescribing, so make sure you follow and share local guidelines and practice. Specifically refer to the New Zealand Palliative Care Handbook (8th Edition). See final slide for a list of resources that support this presentation. Check the repository. Note: Many medications (~25% from UK data) used in palliative care are used outside their normal approved use.

Simple analgesics Paracetamol regularly Codeine phosphate NSAIDS - Diclofenac and naproxen – common examples - Not well tolerated in the older person so must be used with caution

Morphine Mu-opioid receptor agonist Active metabolites Renally excreted – therefore, not for use in renal impairment Subcutaneous morphine - approximately twice as potent as oral morphine - i.e. 20 mg oral = 10 mg subcut Codeine 60 mg = 5-8 mg morphine i.e. 60 mg codeine QID = approx. 5 mg Q4H

Methods of morphine administration Normal Release - Morphine elixir 4 strengths available – be careful to check before administration - Sevredol™ (10 mg & 20 mg tablets only) Controlled release morphine - Note: NOT to be crushed - m-Eslon™ (10 mg, 30 mg, 60 mg,100 mg) can be sprinkled - Arrow-Morphine LA tablets (10 mg, 30 mg, 60 mg, 100 mg) Intraspinal – Step 4 on WHO Ladder

Oxycodone Mu- and kappa- opioid receptor agonist (semi-synthetic) Renally excreted - 19% unchanged, 50% oxymorphone Onset action: 20-30min orally ? Less active metabolites than morphine Notes: Side effects as per morphine ? less vomiting (anecdotally). Use if there is mild-moderate renal impairment although dose reduction should be considered.

OxyNormTM and Oxycodone CR In palliative care, OxyNormTM is generally considered to be twice as potent as morphine when taken orally Subcutaneous oxycodone approximately twice as potent as oral oxycodone i.e. 20 mg oral = 10 mg subcut All preparations are funded cost not excessive useful alternative to morphine when morphine not tolerated or in presence of mild to moderate renal impairment

OxyNormTM and Oxycodone CR contd Normal release: OxyNormTM capsules (5 mg, 10 mg, 20 mg) OxyNormTM oral liquid (5 mg/5 mL) Can be used for titration and breakthrough pain (1/5th – 1/10th of the 24hr dose) Controlled release: Oxycodone CR tablets (5 mg, 10 mg, 20 mg, 40 mg, 80 mg) have a biphasic response - therefore, no need to give immediate release at the same time as slow release dose

Methadone Indications: - Morphine toxicity / unacceptable side effects - Inadequate pain relief with other opioids - Renal failure - Neuropathic pain - Previous narcotic dependence – on maintenance methadone Routes: oral or subcut 5 mg tablet 3 strengths of elixir available – 2 mg, 5 mg and 10 mg per mL - check carefully before administration

Methadone contd Less nausea, constipation and drowsiness than morphine t ½ or half life – 8-75hrs Difficult medication to use – needs medical specialist input

Transdermal Fentanyl Indications - When the oral route is unavailable e.g. dysphagia or severe nausea and/or vomiting - Renal failure - Social (convenience) - Morphine “phobia” - Side effect profile, e.g. less constipation and sedation Pain unresponsive to morphine is unlikely to be responsive to fentanyl, due to also being a mu-opioid receptor agonist Need to titrate with short acting morphine or oxycodone before starting patch - see example on next slide Notes: Point out risk of serotonin toxicity as a result of interaction between Fentanyl and SSRIs. Don’t forget to mention need for breakthrough/prn medication.

Transdermal Fentanyl contd Example of dose comparison when titrating: A 12.5 microgram/hour patch is (approx.) equivalent to 30 mg morphine in a 24hr period

Transdermal Fentanyl contd t ½ or half life - 13-22hrs Steady state plasma concentrations after 36-48hrs Onset of action 12hrs Duration of action 72hrs Contraindication – uncontrolled pain requiring rapid dose titration Patches are 12.5, 25, 50, 75 and 100 mcg/hour – not daily The depot of drug in skin will continue to provide some analgesia for approx.17hrs after a patch is removed

Co-analgesics Antidepressants e.g. nortriptyline Anticonvulsants e.g. sodium valproate, gabapentin, clonazepam Non steroidal anti-inflammatories e.g. diclofenac, naproxen Steroids e.g. dexamethasone Anti-spasmodics e.g hyoscine butylbromide (Buscopan)

Antiemetics Metoclopramide - Dopamine receptor antagonist - Increases peristalsis in upper gut - Contraindicated in complete bowel obstruction and those with Parkinson’s disease - Watch for agitation and akathisia in higher doses, with chronic use, and with presence of renal disease - Oral or subcut Domperidone - Similar to metoclopramide but less extrapyramidal effects - Drug of choice in older person - Oral route Reference regarding metoclopramide caution – agitation/akathisia/tardive dyskinesia Currow, D. C. et al. (2012). Pharmacovigilance in hospice/palliative care: Rapid report of net clinical effect of Metoclopramide. Journal of Palliative Medicine, 15 (10), 1071-1075

Antiemetics Haloperidol Dopamine receptor antagonist, hence not for use in Parkinson’s disease Potent centrally acting antiemetic – very useful for opioid induced nausea, hypercalcaemia and renal failure Can be given subcutaneously Note and reference: Often used to treat delirium due to its ability to be given subcut and to treat multiple symptoms, however, need to be aware that recent studies have recommended against its use for delirium. See reference below: Agar, M.R., et al. (2017). Efficacy of oral risperidone, haloperidol or placebo for symptoms of delirium amongst patients in palliative care: A randomised clinical trial. JAMA Intern Med. 177 (1), 34-42

Antiemetics Cyclizine Oral and subcut routes available - although subcut can be painful Antihistamine, antimuscarinic Indicated for motion sickness, mechanical bowel obstruction, raised intracranial pressure Drowsiness can be profound Can cause confusion in elderly so best to dose reduce Note: Choice of first or second line anti-emetic is often the choice /preference of the doctor prescribing.

Antiemetics Dexamethasone Centrally acting antiemetic Especially useful in liver metastases, raised intracranial pressure, and to reduce vomiting in bowel obstruction Added to first line antiemetics in palliative care Watch for signs of confusion in the older person Can cause insomnia – given in the morning to reduce this effect Can be given subcut - need to watch for volume if given as bolus dose – may need to be divided Notes: Need to consider and plan for reduction and stopping over time. There are other indications for Dexamethasone, including: appetite stimulant Anti-inflammatory properties (adjuvant pain relief) Relief of symptoms in spinal cord compression and superior vena cava obstruction site protector for subcut line.

Antiemetics Levomepromazine Low potency anti-psychotic, blocks a number of differing receptors including dopamine, histamine, adrenergic and serotonin Offers analgesic, antipsychotic, hypnotic and anti-emetic properties in palliative care Most commonly used for intractable nausea and vomiting and severe agitation or delirium in last days of life Side effect – akathisia and significant sedation Note: Choice of anti-emetic is often the choice/preference of the physician.

Midazolam Commonly used for agitation and anxiety associated with dyspnoea Short acting benzodiazepine It is more quickly eliminated from the body compared with clonazepam. Preferred routes in palliative care are subcut, intranasal and buccal

Laxatives Start laxatives when starting opioids Laxsol™ 9/11/2019 Laxatives Start laxatives when starting opioids Laxsol™ - daily or twice daily - up to 3 tablets TDS sometimes necessary - docusate softens and senna stimulates If not effective, add in Lax-Sachets™ as an osmotic – needs to be introduced early (note: requires special authority funding) Kiwi crush will not normally control opioid induced constipation

Suppositories and enemas 9/11/2019 Suppositories and enemas These will not often be required if a good bowel regime has been started - use glycerine suppositories to soften and bisacodyl suppository to stimulate - or use sodium citrate/sodium lauryl sulfoacetate/glycerol (MicrolaxTM enema) – use with caution - or if these are not effective, try an oil retention enema - or use a Fleet™ enema with care Reference: Larkin, P. et al. (2008). The management of constipation in palliative care: clinical practice recommendations. Palliative Medicine, 22 (7), 796-807 Link: Philip Larkin’s palliative care lecture in May 2017 “Palliative approaches to the management of constipation – evidence and clinical implications for practice”. Available on the HNZ website: www.hospice.org.nz/palliative-care-lecture-series/listen-to-lectures

9/11/2019 Precautions Stimulants are contraindicated for people with complete bowel obstruction Bulking agents and high fibre diets are poorly tolerated in the palliative person Lactulose is an osmotic laxative which is poorly tolerated in people who are unable to maintain a high fluid intake

Reassess, reassess, reassess 9/11/2019 Remember to ask Why are you using the medication? What is the most appropriate route? Can we reduce the burden of taking lots of tablets? Are there any contraindications? Have you considered non-pharmacological interventions? Reassess, reassess, reassess

Useful resources and references 9/11/2019 Useful resources and references New Zealand Palliative Care Handbook. (8th Edition). (2016) - http://www.hospice.org.nz/resources/palliative- care-handbook New Zealand Formulary - http://nzformulary.org/ Palliative Care Drugs - http://nzformulary.org/ Medsafe - http://www.medsafe.govt.nz/ The local hospice or community pharmacist Local DHB prescribing guidelines e.g. local hospice or specialist hospital team