Medication Management at End of Life

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1 Medication Management at End of Life Molly Curran, PharmD February 9, 2016 PGY2 Critical Care Pharmacy Resident Department of Pharmacy, University Health System, San Antonio, TX Division of Pharmacotherapy, The University of Texas at Austin College of Pharmacy Pharmacotherapy Education and Research Center, University of Texas Health Science Center at San Antonio Disclosures 2 I acknowledge that I have no actual or potential conflicts of interest or relevant financial relationships with any commercial interest in relation to this CE. 3 Pharmacist Learning Objectives: To describe the role of medication in managing end of life symptoms To explain medication classes important for medical management during end of life care To formulate evidence based recommendations for managing patient symptoms at end of life Pharmacy Technician Objectives: To recognize the common medications used in end of life patient care To describe the administration routes for medications used in palliative care To convert opioid equivalencies for various analgesic medications 1

2 Goals for Patient Care: Rule of Double Effect 4 Alleviate physical and emotional symptoms Achieve the best possible quality of life (QoL) Intended effect Unintended effect Relieves discomfort or suffering Hastens death? Strickland, J.M. (2009) Palliative Pharmacy Care. Unjustified Fears of Double Effect 5 Studies evaluating adequate pain control at end of life: No difference in survival Studies evaluating the use of sedation at end of life: No significant differences in survival One study favored sedation Use symptom relief as means of evaluation Cancer 1999:86: J Palliat Med 1998;1(4) Arch Int Med 2003;163: End of Life Decisions 6 Meet the needs of patient and family May address multitude of concerns about care: Stopping unnecessary interventions Ventilator withdrawal and extubation Aggressive or unnecessary medical therapy Nutrition Provide emotional and spiritual support to prepare or plan for patient death Strickland, J.M. (2009) Palliative Pharmacy Care. 2

3 Health Provider Communication Considerations 7 Spiritual needs Plan Family Goals of Care Patient Centered Caregivers 8 Imminently Dying: Prioritizing Comfort Prepare for transition to comfort care Stop non essential drugs Convert medications aimed at comfort to alternative access routes Subcutaneous, topical, parenteral, rectal Providing support for family, friends, caregivers Address symptoms at end of life Anticipatory medication orders Strickland, J.M. (2009) Palliative Pharmacy Care. 9 What are examples of medications that may be stopped for comfort care patients? A. Atorvastatin B. Lisinopril C. Phenytoin D. Estradiol 3

4 10 Medical Symptom Management End of Life Symptoms 11 Pain Delirium and anxiety Terminal Secretions Dyspnea End of Life: Pain Management 12 Many patients die with treatable pain Up to 80% Minimize iatrogenic sources of pain Use patient self report or validated tools for assessing Behavioral Pain Scale in ICU Critical Care Pain Observational Tool Nonverbal Pain Scale J Palliat Med. 2010; 13(5): J Palliat Med. 2006;9: J Pain Symptom Manage. 2007;34:

Pain Scale Assessment 13 Am J Crit Care 2006; 15(4):420 7. Strategy for Pain Management Adapted from Liverpool Care Pathway 14 Pain? Present Absent Controlled? BMJ 2013;346:f2174.

5 Pain Scale Assessment 13 Am J Crit Care 2006; 15(4): Strategy for Pain Management Adapted from Liverpool Care Pathway 14 Pain? Present Absent Controlled? BMJ 2013;346:f2174. Continue current regimen Add PRN order to anticipate increasing pain Uncontrolled? If Opioid tolerant: Review current analgesia dosage and increase by % depending on severity of pain Give PRN doses as symptoms occur If Opioid naïve: Start PRN Morphine 2 4mg q 15 min to assess usage Prescribe morphine as needed (up to a 1x/hour) Review 24 hour use and consider Infusion if >3 4 doses needed Properties of Common Opioids 15 IV Equiv Dosing Onset to Peak Effect, mins Duration of Effect, hrs Typical Adult Dose Morphine 10 mg mg Fentanyl 100 mcg mcg/kg Hydromorphone 1.5 mg mg Take Home Point #1: If pain well controlled, consider continuing current regimen or using equi analgesic dose Crit Care Med 2008;36(3)

6 Opioid Metabolism: Focus on Morphine 16 Image from: Acta Anaesthesiol Scand 1997 Jan;41(1 Pt 2): When administered orally, undergoes 1 st pass metabolism to produce: Active metabolite Morphine 6 glucoronide Inactive metabolite Morphine 3 glucoronide Contributes to neurotoxicity All opioids undergo hepatic metabolism Metabolites are renally cleared Consider dose reduction/decreased frequency if side effects 17 Alternative Routes: Sublingual Opioids Advantages: Rapidity of onset Bypass 1 st pass metabolism Intensity/duration analgesia Smaller side effect profile Non invasive profile Ease of administration Disadvantages Unpalatable Burning sensation Need to retain medication for minutes Pharmacol Res Commun 1982;14: Am J Hosp Care 1987;4: Am J Hosp Care 1988;5:17 8. Pharmacokinetics: Sublingual Morphine 18 Intervention Outcomes Misc McQuay et al. n = 5 Dose: 10 mg Retained: 5 min Population: Chronic opioid use Mean bioavailability: 61% (10 100%) Measured morphine in expectorant (F = 51%) Pannuti et al. n= 8 Dose: 10 mg Retained: 10 min Population: Advanced cancer No statistically significant differences Allowed patients to swallow SL dose confounds results Weinberg et al. n= 10 Dose: 15 mg tablet Population: Healthy volunteers Mean absorption: 22% Mean bioavailability : 9 ± 11.9% Retention time unknown Osborne et al. n= 10 Dose: 11.7 mg tablet Retained: Until dissolution Population: Healthy volunteers No statistically significant difference from PO morphine (21.9% v. 20.% bioavailability) Longer Tmax and Cmax 6

19 Pharmacodynamics: Sublingual Morphine

surgical patients Average pain scores (0 5

using SL opioids, avoid doses greater than

7 19 Pharmacodynamics: Sublingual Morphine Intervention Outcomes Misc Pannuti et al. n= 8 Dose titrated to effect Interval: Every 4 hours as needed over 5 weeks Population: Advanced cancer Mean pain reduction (0 10 VAS): 7.8 to 2.7 Statistically significant advantages: Rapidity/intensity of analgesia Nonsignificant reduction in constipation/vomiting Engelhardt and Crawford. n= 14 Dose: 0.1 mg/kg solution Population: Pediatric surgical patients Average pain scores (0 5 rating scale) SL route: 2.3 ±0.5 IV route: 2.5 ±0.6 All patients received concurrent NSAID therapy which may confound results 20 Alternative Routes: Sublingual Opioids Other opioids have been studied for sublingual administration: Methadone Fentanyl SL bioavailability reported is highly variable Take Home Point #2: If using SL opioids, avoid doses greater than 2 ml because may leak out of sublingual space J Palliat Med. 2007;10(2): What is the equivalent dose of 10mg IV morphine in mcg of IV fentanyl? A. 30 mg B. 30 mcg C. 100 mcg D mcg 7

Alternative Routes: Rectal Opioids 22 Highly bioavailable absorption in lower rectum bypass 1 st pass metabolism Upper rectum absorption undergoes 1 st pass metabolism Dose similar to oral opioids

compromised Capc.org. Fast Fact #257 J Pain Symptom Manage. 1996;11(6):378 87.

8 Alternative Routes: Rectal Opioids 22 Highly bioavailable absorption in lower rectum bypass 1 st pass metabolism Upper rectum absorption undergoes 1 st pass metabolism Dose similar to oral opioids due to anastomses Any immediate release tablet or solution can be given rectally Take Home Point #3: May give IR opioid tablets/solution/parenteral solution (<60 ml) per rectum if PO route compromised Capc.org. Fast Fact #257 J Pain Symptom Manage. 1996;11(6): Alternative Routes: Subcutaneous Opioids May be administered continuously or as needed Conversion ratio from IV:SubQ not well established Morphine appears to be 1:1 Adverse effects include skin irritation, itching, site bleeding Change needle if occurs Take Home Point #4: SubQ tissue allows for absorption of up to 3mL/hr, so consider intrinsic potency of opioid if using this route Capc.org. Fast Fact #28 Cancer. 1988;62: Alternative Routes: Transdermal Fentanyl Therapeutic blood levels achieved hours after patch removal Continue to release drug for up to 24 hours after removal May not be sufficient means of pain control for patient in last hours Absorption effected by fevers/cachexia Capc.org. Fast Fact #28 J Pain Symptom Manage. 1996;11(6):

9 What are alternative routes you can consider in patients without IV access? A. Subcutaneous B. Sublingual C. Transdermal D. Rectal E. All of the Above 25 End of Life Symptoms Pain Delirium and anxiety Terminal secretions Dyspnea 26 End of Life: Anxiety and Delirium 27 State of apprehension and fear Delirium Hyper or hypo active Terminal agitation No reversible causes present May indicate distress: Physical Psychological Existential BMJ 2013;346:f2174. Clin Geriatr Med 20(2004)

10 Considerations in Terminal Delirium 28 Check medication list: Anti cholinergics Sedatives Hypnotics Opioids Consider other etiologies Withdrawal CNS involvement Metabolic derangements Neuroleptics are drugs of choice for treatment: Haloperidol Olanzapine Quetiapine Risperidone Scant data for atypical agents QTc interval consider risks and benefits Benzodiazepines (BZD) may precipitate paradoxical response Capc.org. Fast Fact #60. Am J Psych. 1996; 153: Anxiety in Imminent Death 29 Common in patients facing life threatening illnesses Address and identify reversible causes Drugs: corticosteroids, stimulants, etc. BZD monotherapy for patients with days to weeks For patients with months, antidepressants are preferred Consider adjunctive BZD for first weeks of therapy Consider rebound anxiety in patients previously on oral BZD J Palliat Med. 2005; 8: Capc.org. Fast Fact #145. Practical Considerations: Benzodiazepine Therapy 30 Benzodiazepine Equivalent Oral Dose (mg) Half life (hr) Alprazolam Lorazepam Clonazepam Diazepam Take Home Point #5: If patient previously on BZD, consider equi potent dosing if changing route/drug (PR, IV, SubQ) 10

End of Life Symptoms Pain Delirium and anxiety Terminal

ability to clear/swallow oral secretions Decline of gag

tree secretions Gurgling, Crackling, Rattling Terminal

On side Semi prone Medication therapy Anticholinergics MOA:

11 End of Life Symptoms Pain Delirium and anxiety Terminal secretions Dyspnea 31 End of Life: Terminal Secretions 32 Lose ability to clear/swallow oral secretions Decline of gag reflex/reflexive clearing Accumulation of tracheobronchial tree secretions Gurgling, Crackling, Rattling Terminal Secretions: Treatment 33 Repositioning for postural drainage On side Semi prone Medication therapy Anticholinergics MOA: Relax bronchial muscles and open airways Dry mucus secretion and slow ciliary passage 11

Treatment: Anticholinergics 34 Anticholinergic

brain barrier (BBB) Quaternary: do not cross BBB

muscarinic receptors Am J Hosp Palliat Med

Anticholinergic Toxicity 35 Ileus Psychosis

Palliat Med Treatment Options: Anticholinergics

4 mg IV every 8 hours PRN Crosses BBB Increased

BBB Onset 6 to 8 hours Steady state at 24 hours Up

12 Treatment: Anticholinergics 34 Anticholinergic drugs are divided into: Tertiary: cross blood brain barrier (BBB) Quaternary: do not cross BBB Implications on side effect profile Bind muscarinic receptors Am J Hosp Palliat Med 2012;30(5) Anticholinergic Toxicity 35 Ileus Psychosis Confusion Dry skin Tachycardia Delirium Hypertension Blurred vision Mydriasis Anticholinergic Toxicity Hyperthermia Am J Hosp Palliat Med 2012;30(5) Treatment Options: Anticholinergics 36 Medication Dose/Route Titration Clinical Pearls Atropine 1% eye drops Scopalamine patch Glycopyrrolate (Robinul ) 1 2 drops SL PRN Every 6 hours PRN 1 patch (1.5 mg base delivers 1 mg drug) 0.2 to 0.4 mg IV every 8 hours PRN Crosses BBB Increased risk of CNS side effects Every 72 hours Crosses BBB Onset 6 to 8 hours Steady state at 24 hours Up to every 6 hours PO absorption erratic Can be given SubQ Hyoscyamine mg or 0.25 mg PO PRN Am J Hosp Palliat Med, 2012;30(5) Crosses BBB Onset 30 min Available in SL tablets 12

37 Pharmacodynamics: Anticholinergic Therapy Likar et al,

placebo n = 13 Terminal cancer/cognitive dysfunction IV

4 mg every 6 hours versus bolus scopalamine HBr 0.

Liverpool Care Pathway n = 72 (36 in each arm) Advanced

4 SubQ followed by continuous bolus drug infusions

12 hours *Small sample size Full response in

*Observer bias, unbalanced populations Wien Klin

Contraindications to anticholinergic use: Closed angle

delirium Take Home Point #6: When selecting an agent for

13 37 Pharmacodynamics: Anticholinergic Therapy Likar et al, 2008 Hugel et al, 2006 Study (n) Methods Randomized, no placebo n = 13 Terminal cancer/cognitive dysfunction IV glycopyrrolate 0.4 mg every 6 hours versus bolus scopalamine HBr 0.5 mg every 6 hours Effectiveness of symptom control in Liverpool Care Pathway n = 72 (36 in each arm) Advanced cancer SubQ glycopyrrolate 0.2 mg versus hyoscine HBr 0.4 SubQ followed by continuous bolus drug infusions Outcomes Glycopyrrolate superior to scopolamine HBr over 12 hours *Small sample size Full response in glycopyrrolate group versus 22% in hyoscine response *Observer bias, unbalanced populations Wien Klin Wocheneschr 2008;120(21 22): J Palliat Med 2006;9(2): Patient Considerations: Anticholinergics Contraindications to anticholinergic use: Closed angle glaucoma Ileus Caution in patients with pre existing delirium Take Home Point #6: When selecting an agent for terminal secretions, glycopyrrolate does not cross BBB and may result in less CNS effects Am J Hosp Palliat Med, 2012;30(5) End of Life Symptoms 39 Pain Delirium and anxiety Terminal secretions Dyspnea 13

End of Life: Dyspnea 40 Described as: Short of breath Suffocating Choking Drowning Due to: Increased respiratory hindrance Abnormality of respiratory muscles Increased ventilatory demand

14 End of Life: Dyspnea 40 Described as: Short of breath Suffocating Choking Drowning Due to: Increased respiratory hindrance Abnormality of respiratory muscles Increased ventilatory demand Treatment: Dyspnea 41 Goal: Decrease discomfort Non pharmacologic strategies: Improve air circulation Breathing exercises Positioning Medications Opioids Anxiolytics if anxiety related J Palliat Med 2012;15: Opioids for Dyspnea 42 Improve sensation of breathlessness at low doses Exact mechanism unknown Distinct from respiratory depression at high doses No advantage of inhalation therapy over PO/IV Take Home Point #7: While most opioids may be help with dyspnea, methadone is not effective for this indication BMJ 2013;346:f2174. The Cochrane Database System,

15 Anxiolytics for Dyspnea 43 Second line agents for dyspnea Effective for patients with anxiety disorder Treatment of anxiety ameliorate dyspnea Lorazepam may be given PO, SL, or SubQ Take Home Point #8: Anxiolytics are not first line therapy for patients complaining of breathlessness BMJ 2013;346:f2174. J Palliat Med 2012;15: Standardizing Symptom Orders 44 Wide variation exists in the palliative care delivered at End of Life Recent research has looked at Comfort Care Order Sets (CCOS) Purpose to facilitate comfort care interventions BEACON Trial, 2014: Multimodal approach to end of life care increased comfort interventions Impact of Standardized Palliative Care Order Set of End of Life Care, 2011: Addition of order set significantly improved adherence to accepted endof life interventions J Palliat Med 2011;14(3): J Gen Intern Med 29(6): Example of CCOS 45 Acetaminophen 650 mg PO/PR q4h PRN T>101 F For constant pain, give (suggest Morphine SR) at PO BID For intermittent pain or shortness of breath give: Morphine sulfate mg PO q 2h PRN (suggest starting at 5mg) If NPO, give morphine sulfate mg IV/SubQ q 2h PRN (suggest starting at 2mg) For anxiety, give lorazepam 0.5 mg IV/PO q6h PRN For constipation, senna/docusate 2 tablets PO QHS For nausea/delirium, haloperidol 1 mg PO/IV q 4h PRN For excessive secretions hyoscyamine mg SL q 4h PRN J Gen Intern Med 29(6):

46 What are the potential advantages to having an inpatient palliative care order set? A. Less wait time for medications B. May anticipate patient needs C. Allow for focused care on communication D.

48 Opioids BZDs Anticholinergics Neuroleptics Morphine Concentrated PO solution: 20 mg/ml Injection: 2 15mg/mL PO Solution: 2 mg/ml Hydromorphone Injection: 2 or 10 mg/ml Fentanyl Injection: 0.

Diazepam Injection: 5 mg/ml Clonazepam Suspension: 0.1 mg/ml Tablet: 0.5,1, 2mg Alprazolam Tablet: 0.25, 0.5, 1 mg Glycopyrrolate Injection: 0.

16 46 What are the potential advantages to having an inpatient palliative care order set? A. Less wait time for medications B. May anticipate patient needs C. Allow for focused care on communication D. All of the above 47 Practical Considerations What s on formulary? 48 Opioids BZDs Anticholinergics Neuroleptics Morphine Concentrated PO solution: 20 mg/ml Injection: 2 15mg/mL PO Solution: 2 mg/ml Hydromorphone Injection: 2 or 10 mg/ml Fentanyl Injection: 0.05 mg/ml Transdermal: 25, mcg Methadone PO solution: All floors Injection: NONE Lorazepam Concentrated PO solution: 2 mg/ml Injection: 2, 4 mg/ml Midazolam Injection: 1 mg/ml Syrup: 2 mg/ml Diazepam Injection: 5 mg/ml Clonazepam Suspension: 0.1 mg/ml Tablet: 0.5,1, 2mg Alprazolam Tablet: 0.25, 0.5, 1 mg Glycopyrrolate Injection: 0.2 mg/ml Atropine Ophthalmic Soln: 1% Scopalamine Patch: 1.5 mg base Hyoscyamine Elixir: mg/5 ml Tablet (SL, chewable, PO): mg Haloperidol Concentrated PO: 2 mg/ml Injection (lactate): 5mg/mL Tablet: 0.5, 1, 2, 5, 10, 20 mg Olanzapine Tablet: 2.5, 5, 7.5, 10, 15, 20 mg ODT: 5, 10, 15, 20 mg Quetiapine SR tablets: 25, 50, 100, 200, 300, 400 mg Risperidone ODT: 0.5, 1, 2, 3, 4 mg PO Solution: 1 mg/ml Tablet: 0.25, 0.5, 1, 2, 3, 4 16

Hydromorphone Injection: All floors Fentanyl Injection: All floors except 5ACU and PSYCH Methadone PO solution: 1mg/mL Injection: 10 mg/ml

Clonazepam Suspension: None Tablet: All floors Alprazolam Tablet: All floors Glycopyrrolate Injection: 8ACU, 8ICU Atropine Ophthalmic Soln: None

(lactate): All floors Tablet: 5ACU, 6ACU, 8ACU, 9ACU, 9ICU Olanzapine Tablet: All floors ODT: All floors except 9WEST Quetiapine SR tablets: All

Anticipatory orders especially important if: Not stocked in PXYIS STAT orders to be verified and sent by pharmacy within 1 hours Do not call

17 What s in my PXYIS? 49 Opioids BZDs Anticholinergics Neuroleptics Morphine Concentrated PO solution: 8ACU Injection: All floors PO Solution: All floors except 9ICU Hydromorphone Injection: All floors Fentanyl Injection: All floors except 5ACU and PSYCH Methadone PO solution: 1mg/mL Injection: 10 mg/ml Lorazepam Concentrated PO solution: None Injection: All floors Midazolam Injection: All floors Syrup: NONE Diazepam Injection: All floors ^ICU Clonazepam Suspension: None Tablet: All floors Alprazolam Tablet: All floors Glycopyrrolate Injection: 8ACU, 8ICU Atropine Ophthalmic Soln: None Scopalamine Patch: 5ICU, 6ACU, 8ACU Hyoscyamine Elixir: None Tablet (SL, chewable, PO): 8ACU Haloperidol Concentrated PO:: NONE Injection (lactate): All floors Tablet: 5ACU, 6ACU, 8ACU, 9ACU, 9ICU Olanzapine Tablet: All floors ODT: All floors except 9WEST Quetiapine SR tablets: All floors Risperidone ODT: All floors except 5ICU, 9WEST PO Solution: NONE Tablet: All floors Current as of Medication Orders 50 Anticipatory orders especially important if: Not stocked in PXYIS STAT orders to be verified and sent by pharmacy within 1 hours Do not call unless <1 hour Routine orders to be verified and sent by pharmacy within 2 hours Final Considerations 51 End of life is an unpredictable process Evaluate patient s comfort level bedside Medications are one part of the treatment Anticipating end of life needs may provide more timely care for patients 17

18 Thank You 52 Dr. Katie Stowers Laurajo Ryan, PharmD Bryson Duhon, PharmD Questions? 53 Secret CE Codes For Pharmacists: WG8i For Technicians: k8ic 54 18

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