Find out more online: Opioids and anti-emetics in palliative care Dr Claire Curtis Consultant in Palliative Medicine

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

Find out more online: Morphine

Find out more online: 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

Find out more online: 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

Find out more online: Opioid adverse effects ● Management strategy ●Dose reduction ●Therapy to treat adverse effect ●Opioid switching ●Adjuvant analgesics to reduce opioid requirement

Find out more online: 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

Find out more online: 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

Find out more online: 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

Find out more online: 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

Find out more online: 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

Find out more online: 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

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

Find out more online: Remember ● Rescue medication

Find out more online: Diamorphine

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

Find out more online: 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

Find out more online: Oxycodone

Find out more online: 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 ● % excreted unchanged by kidneys – can accumulate in RF

Find out more online: 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

Find out more online: Transdermal fentanyl

Find out more online: 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

Find out more online: 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)

Find out more online: 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

Find out more online: 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)

Find out more online: Alfentanil

Find out more online: Alfentanil ● Parenteral only (500mcg/ml) ● Synthetic derivative of fentanyl ●More rapid onset <5min ●shorter duration 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

Find out more online: Alfentanil ● Potency ●Sc alfentanil = 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

Find out more online: Buprenorphine

Find out more online: 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

Find out more online: 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

Find out more online: 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

Find out more online: 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

Find out more online: Hydromorphone

Find out more online: 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

Find out more online: Transmucosal fentanyl

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

Find out more online: Nausea and Vomiting

Find out more online: 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

Find out more online: 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

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

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

Find out more online: 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

Find out more online: Metoclopramide

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

Find out more online: 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

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

Find out more online: Cyclizine

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

Find out more online: 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

Find out more online: Haloperidol

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

Find out more online: 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

Find out more online: Levomepromazine

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

Find out more online: 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)

Find out more online: Ondansetron

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

Find out more online: 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)

Find out more online: 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

Find out more online: 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

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

Find out more online: “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

Find out more online: 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

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Find out more online: Summary

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

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

Find out more online: References/useful resources ● West Midlands Palliative Care Physicians: Guidelines for the use of drugs in symptom control. Jan ● Palliative Care Guidelines Plus ● ● drugs.com ● Palliative care formulary. 3 rd Ed. Twycross, Wilcock