BEAHERO TO A DYING PATIENT: SYMPTOM MANAGEMENT AT END- OF LIFE.

Robert G. Wahler, Jr., Pharm.D., BCGP, FASCP, CPE Clinical Assistant Professor, UB SPPS Director, Clinical Pharmacy Services, Niagara

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 2019 Wahler RG LEARNING OBJECTIVES

1. Identify common symptoms experienced by patients with advanced illness. 2. Select or recommend medication options for specific palliative symptoms. 3. Discuss various pharmacologic interventions for common symptoms. 4. Define treatment measures in the last hours of life.

2 INTRODUCTION

 2.8 million death/year in US, 1.4 million in hospice.  It is important to address and manage each end-of-life symptom to improve the quality of life for the patient.  An interdisciplinary team approach is beneficial throughout the care of the patient. This is evident when addressing more psychologically based symptoms, such as .

3 INTRODUCTION

 The ASHP Guidelines on the Pharmacist's Role in Palliative and Hospice Care - Essential Clinical and Administrative Roles  Direct patient care  Optimize the outcomes of symptom management and patients through the expert provision of evidence-based, patient-centered medication therapy as an integral part of an interdisciplinary team  Serve as an authoritative resource on the optimal use of medications in symptom management and palliative care  Anticipate transitions of care when recommending, initiating, modifying, or discontinuing pharmacotherapy for pain and symptoms  Medication order review and reconciliation  Manage and improve the medication-use process in patient care settings  Education and medication counseling  Demonstrate excellence in the provision of medication counseling to patients, caregivers, and families  Administrative roles 4  Ensure safe use of medications in the treatment of pain and symptoms  Medication supply chain management Herndon CM, Nee D, Atayee RS, Craig DS, Lehn J, Moore PS, Nesbit SA, Ray JB, Scullion BF, Wahler RG, Waldfogel J. Am J Health Syst Pharm 2016;73(17):1351-1367. SELF-ASSESSMENT QUESTION

 Which common LTC admission diagnosis is the highest ranked reason for hospice admission? A. Cancer B. Heart Failure C. Dementia D. COPD E. Cerebrovascular Disease Conditions qualifying for hospice admission Conditions requiring palliation

TABLE 2—THE TOP TWENTY PRINCIPAL HOSPICE DIAGNOSES, FY 2017 (SIMPLIFIED) RankReported principal diagnosis Count Percentage 1 All Alzheimer's & Dementia 260,085 32.7% 2 All Heart Disease 141,116 17.7% 3 All Cancer 120,746 15.2% 4 All COPD 111,305 14.0% 5 All Cerebrovascular Disease 71,205 8.9% 6 Parkinson’s disease 40,186 5.0% 7 ESRD 21,549 2.7% 8 Kidney disease, not End-Stage 15,632 2.0% 9 Sepsis, unspecified organism 14,012 1.8% CHANGES DURING THE DYING PROCESS Change Manifested by/Signs of: Fatigue, weakness Decreasing function, hygiene Inability to move around bed Inability to lift head off pillow Cutaneous ischemia Erythema over bony prominences Skin breakdown, wounds Decreasing appetite/food Anorexia intake, wasting Poor intake Weight loss, muscle and fat, notable in temples

9 Medscape Internal The Last Hours of Living: Practical Advice for Clinicians Emanuel, L., Ferris, F. D., von Gunten, C. F., & Von Roenn, J. H. March 24, 2015 (http://www.medscape.com/viewarticle/716463_2 Accessed 4-2-15) CHANGES DURING THE DYING PROCESS Change Manifested by/Signs of: Cardiac dysfunction, Tachycardia renal failure Hypertension followed by hypotension Peripheral cooling Peripheral and central cyanosis (bluish color of extremities) Mottling of the skin (livedo reticularis) Venous pooling along dependent skin surfaces Dark urine 10 Oliguria, anuria CHANGES DURING THE DYING PROCESS Change Manifested by/Signs of: Neurologic dysfunction, including: Decreasing level of Increasing drowsiness consciousness Difficulty awakening Unresponsive to verbal or tactile stimuli Decreasing ability Difficulty finding words to communicate Monosyllabic words, short sentences Delayed or inappropriate responses Verbally unresponsive Terminal delirium Day-night reversal Confusion Agitation, restlessness 11 Purposeless, repetitious movements Moaning, groaning CHANGES DURING THE DYING PROCESS Change Manifested by/Signs of: Respiratory Change in respiratory rate—increasing dysfunction first, then slowing Decreasing tidal volume Abnormal breathing patterns—apnea, Cheyne-Stokes respirations, agonal breaths Loss of ability to Dysphagia swallow Coughing, choking, aspiration (Opportunity for Loss of gag reflex Pharmacists to “shine”) Buildup of oral and tracheal secretions Gurgling (“death rattle”) 12 CHANGES DURING THE DYING PROCESS Change Manifested by/Signs of: Loss of Incontinence of urine or bowels sphincter Maceration of skin control Perineal candidiasis Pain Facial grimacing Moaning Tension in forehead, between eyebrows Loss of ability to Eyelids not closed close eyes Whites of eyes showing (with or without pupils visible) Rare, unexpected events: Bursts of energy just before death occurs, the "golden glow"13 Aspiration, asphyxiation TWO ROADS TO DEATH The Difficult Road Confused Tremulous

Restless Hallucinations Normal Pain

Dyspnea Mumbling delirium Sleepy Anxiety

Lethargic Nausea/Vomiting Myoclonic jerks

The Usual Road Obtunded “Gurgling” Seizures

Semicomatose

Comatose 14

Adapted from: The Last Hours of Living: Practical Advice for Clinicians Emanuel, L., Ferris, F. D., von Gunten, C. F., & Von Roenn, J. H. March 24, 2015 Dead (http://www.medscape.com/viewarticle/716463_2 Accessed 4-2-15) PORTMANTEAU –DESIRABLE PROPERTIES

1. Multiple therapeutic effects 2. Minimal drug interactions 3. Multiple routes of administration 4. Wide therapeutic window 5. Cost-effective 6. Convenient dosing schedule 7. Dose response and favorable ceiling effect

Dickerson. European Journal of Palliative Care 1999; 6:130-136. PALLIATIVE CARE TOOLKIT  “intensol” = concentrated liquid  Morphine liquid (Roxanol) 100mg/5ml (aka 20mg/ml)  Methadone liquid 10mg/ml  Hydromorphone liquid 1mg/ml  Oxycodone liquid 20mg/ml  liquid 2mg/ml (buccal admin of tabs)  Alprazolam liquid 1mg/ml (also ODT)  Haloperidol liquid 2mg/ml  Atropine 1% ophth. gtts  Dexamethasone liquid 1mg/ml  Ondansetron ODT  Metoclopramide liquid 5mg/5ml and ODT ($$$) 16 De Lima L, Doyle D. The International Association for Hospice and Palliative Care List of Essential for Palliative Care. Journal of Pain & Palliative Care Pharmacotherapy. 2009;21(3):29-36. Dickerson D. The 20 essential drugs in palliative care. European Journal of Palliative Care. 1999;6:130-136. WHO'S CANCER PAIN LADDER FOR ADULTS

• “… consistently failed to provide sufficient relief to 10%–20% of advanced cancer patients with pain, particularly in cases of neuropathic pain and pain associated with bone involvement”* *Nersesyan, H., & Slavin, K. V. (2007). Therapeutics and Clinical Risk Management, 3(3), 381–400. X • Two Step Versus the Standard Three Step Approach of the WHO Analgesic Ladder for Cancer Pain Relief trial World Health Organization • Remove Step 2? http://www.who.int/cancer/pa lliative/painladder/en/ European Palliative Care Research Centre TVT trial https://www.ntnu.edu/prc/tvt-study-information Accessed 4-1-2017 Accessed 4-1-2017 WHERE TO START

 Base the initial treatment on the severity of pain the patient reports.  Mild – Non- analgesic  Moderate – Opioid  Severe (Pain emergency)– Opioid  Provide Rx.  PRN analgesic medication  “Take the medication if unexpected pain occurs.”  “Call for an appointment to evaluate the pain problem.”  Begin a bowel regimen.

Miaskowski, C. et. al. (2004). Guideline for the Management of Cancer Pain in Adults and Children, APS Clinical Practice Guidelines Series, No. 3. Glenview, IL: American Pain Society. The Dosing Frequency Conundrum

Suffering

3 hrs

2.5 hrs

Whitten, et al. The Permanente Journal 2005;9(4):9-18. 19 19 THE NEXT STEP

 “Administer a long-acting opioid on an around-the- clock basis, along with an immediate-release opioid to be used on an as-needed basis, for breakthrough pain once the patient's pain intensity and dose are stabilized.”

Miaskowski, C. et. al. (2004). Guideline for the Management of Cancer Pain in Adults and Children, APS Clinical Practice Guidelines Series, No. 3. Glenview, IL: American Pain Society. BREAKTHROUGH PAIN (BTP) MEDICATIONS

 Which opioid to give?  Same as long-acting?  How much to give?  Start at 10-20%1,2 of total daily dose  Example: 60mg ER Morphine  5-10mg PRN BTP  “Allow rescue doses of short-acting of 10% to 20% of the 24-hour total of long-acting or regularly scheduled oral opioid dose up to every 1 hour as needed” - NCCN  How often to give?  Based on pharmacokinetics, but no longer than q3h intervals  When to change long-acting meds?  Patient dependent

1. Miaskowski, C. et. al. (2004). Guideline for the Management of Cancer Pain in Adults and Children, APS Clinical Practice Guidelines Series, No. 3. Glenview, IL: American Pain Society. 2. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Adult Cancer Pain V.1.2017. © 2017 National Comprehensive Cancer Network, Inc. 3. Ashburn M, Lipman A, et. al. Principles of Analgesic Use in the Treatment of Acute Pain and Cancer Pain, Glenview (IL): American Pain Society (APS); 2003. METASTATIC BONE PAIN

 NSAIDs & Cox-2-Inh  Corticosteroids • Pros • Anti-inflammatory • Start dexamethasone • Useful for mild to moderate pain 2-16mg/day (PO or IV) • Up to ~30mg daily • Adjunctive • Anti-emetic • Cons • Appetite stimulation • Ceiling effect • Antidepressant effects - • Toxicity (esp. elderly) “stimulatory” • Significant long-term • GI side effects (mitigated) • Renal

• Cardiac OPIOID ROUTES OF ADMINISTRATION

 Non-Parenteral  Parenteral • PO/SL/Transbuccal • IM • Inhaled • IV

• Intranasal • Continuous infusion* • Rectal • Sub-Q site • Topical • Low volume infusion • PCA • Intrathecal

*NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Adult Cancer Pain V.1.2017. © 2017 National Comprehensive Cancer Network, Inc. DYSPNEA

 Step 1  Treat underlying cause if possible.  Step 2  Ipratropium/Albuterol (DuoNeb) ± dexamethasone  Step 3  Morphine (any opioid) ± dexamethasone  Step 4  Morphine AND

Chlorpromazine or

Diazepam or

25 DYSPNEA -OPIOIDS

 Help relieve sensation of  In the opioid naive patient, low doses of oral (2.5 – 5 mg) or parenteral morphine (1 – 2 mg), provide relief for most patients.  More frequent dosing is more effective than higher doses if dyspnea not adequately treated.  Generally requires lower doses than necessary for treatment of pain.  “Start low, go slow.”

Johnson, et. al. Am J Hosp Palliat Care. 2016;33(2): 194-200. Rocker, et. al. Thorax 2009;64(10): 910-915. MECHANISM OF OPIOIDS FOR DYSPNEA

 Uncertain.  May diminish the chemoreceptor response to hypercapnia and hypoxia.  May cause vasodilation, resulting in decreased dyspnea due to the resulting reduction in preload and pulmonary congestion.  May result in a decrease in anxiety and the subjective sensation of dyspnea through a central effect.  May treat underlying pain that is causing increased respiratory drive.  No difference between morphine and other short- acting opioids.

Zebraski et al. Life Sciences 2000;66(23): 2221-2231. LONG-ACTING OPIOIDS FOR DYSPNEA

 Trial of 48 opioid-naïve COPD patients  Randomized: 20 mg LA morphine or placebo x 4 days  Significant improvements in subjective dyspnea scores on VAS  LA morphine for refractory breathlessness  83 patients: COPD, cancer and interstitial lung  62% derived benefit; NNT=2, NNH=5

Abernethy, et al. BMJ 2003;327(7414): 523-528. Currow, et al. J Pain and Symptom Manage. 2011;42(3): 388-399. EXPERT RECOMMENDATIONS

 Low-dose opioids for relief of dyspnea  American Thoracic Society (ATS)1,2  American College of Chest Physicians3  American College of Physicians4  National Comprehensive Cancer Network (NCCN)5

1. Lanken, et al. Am J Respir Crit Care Med. 2008;177(8): 912-927. 2. Parshall, et al. Am J Respir Crit Care Med. 2012;185(4): 435-452. 3. Mahler, et al. Chest. 2010;137(3): 674-691. 4. Qaseem, et al. Ann Intern Med 2008;148(2):141-146. 5. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Adult Cancer Pain V.1.2017. © 2017 National Comprehensive Cancer Network, Inc. ANXIETY DELIRIUM  Worry, Tense, Unable to  Disorientation, relax. hallucinations, aggressive  Step 1– non-pharm  Step 1  Step 2– short-term  Lorazepam  Haloperidol  Alprazolam  Step 2  Amitriptyline (w/  Haloperidol + lorazepam depression) (sedation required)  Step 2- long-term  Step 3  Buspirone  SSRI  Haloperidol + Midazolam Escitalopram (Versed) or (Lexapro) chlorpromazine Sertraline (Zoloft) (Thorazine)  Mirtazepine (w/  Agitation in terminal depression, insomnia stages and anorexia) 30 CONUNDRUM

 Necessary at EOL.  Lorazepam With Haloperidol vs Haloperidol Alone  90 randomized patients (mean age, 62 years; women, 42 [47%]),  58 (64%) received the study medication and 52 (90%) completed the trial.  Lorazepam + haloperidol resulted in:  reduction of Richmond Agitation-Sedation Scale (RASS) score at 8 hours (−4.1 points) vs. placebo + haloperidol (−2.3 points) (mean difference, −1.9 points [95%CI, −2.8 to −0.9]; P < .001).  less median rescue neuroleptics (2.0mg) vs. placebo + haloperidol group (4.0mg) (median difference, −1.0mg [95%CI, −2.0 to 0]; P = .009)  Perceived to be more comfortable  blinded caregivers: (84% for the lorazepam + haloperidol group vs 37% for the placebo + haloperidol group; mean difference, 47%[95%CI, 14%to 73%], P = .007;  nurses: 77% for the lorazepam + haloperidol group vs 30% for the placebo + haloperidol group; mean difference, 47%[95%CI, 17%to 71%], P = .005).

 Hui D, Frisbee-Hume S, Wilson A, et al. Effect of Lorazepam With Haloperidol vs Haloperidol Alone on Agitated Delirium in Patients With Advanced Cancer Receiving Palliative Care: A Randomized Clinical Trial. JAMA. 2017;318(11):1047-1056.

 Application to LTC.  Beers criteria – “outside of the palliative care and hospice setting.” 31  Herndon C, Wahler R, Jr., McPherson ML. Beers Criteria, the Minimum Data Set, and Hospice. J Am Geriatr Soc. 2016;64(7):1519-1520.

 Personal story NAUSEA AND VOMITING

 Gut wall  Area postrema  Gastric irritants  Morphine, digoxin  Abdominal radiotherapy  Hypercalcemia/ uremia  Intestinal distention  Clonidine  Cytotoxic chemo  Cytotoxic chemo  Treatments  Treatments  Step 1  Step 1

 H2 antagonist  Haloperidol  Proton-Pump Inhibitor  Metoclopramide  Step2  Step 2  Metoclopramide  Step 1 + dexamethasone  Step 3  pamidronate  Ondansetron (Zofran) (Aredia)for hypercalcemia  Step 3  Ondansetron + 32 dexamethasone NAUSEA AND VOMITING

 Cerebral cortex  Vestibular nuclei  Fear/anxiety  Movement  Raised intracranial  Vertigo pressure  Vestibular nuclei  Hyponatremia  Step 1  Cerebral cortex  Diphenhydramine  Step 1 (Benadryl)  Dexamethsone  Dimenhydrinate  Step 2 (Dramamine)  Amitriptyline  Step 2  Haloperidol  Meclizine (Antivert) or Cyclizine (Marezine)  Lorazepam  Step 3  Step 3  Glycopyrrolate  Limited free water ± (Robinul)  3% saline ±  Scopolamine  haloperidol 33 COUGH

 Wet vs dry, productive vs non-productive  Step 1 – treat underlying cause  Step 2 – Promote production  Nebulized saline and/or guaifenesin  Step 3 – Suppress cough  Morphine, hydrocodone, dextromethorphan, benzonatate  Step 4  Dexamethasone (irritating tumor)  Glycopyrrolate/atropine (terminal secretions)  N-acetylcysteine (nebulized or oral – thick mucous)

 Step 5 – nebulized lidocaine, gabapentin, others. 34  Estfan B, LeGrand S. Management of cough in advanced cancer. The journal of supportive oncology. 2004;2(6):523-527.  Molassiotis A, Smith JA, Bennett MI, et al. Clinical expert guidelines for the management of cough in lung cancer: report of a UK task group on cough. Cough. 2010;6(9):38092. TERMINAL SECRETIONS -

 Gurgling, “death rattle”  Atropine 1% ophth gtts SL 2-3 q2-3 h PRN  Not earlier – dry mouth  Also  Scopolamine patch  Glycopyrrolate

35 PALLIATIVE SEDATION

 “When terminally ill, conscious patients experience intolerable symptoms that cannot be relieved even by expert palliative care, administering sedatives to induce unconsciousness may be an acceptable last resort to relieve suffering.”  Doctrine of Double Effect  Moral distinction

Intention (relieve symptoms) vs. foreseen but unintended side effect (death)

36 Kirk TW, Mahon MM, Palliative Sedation Task Force of the National H, Palliative Care Organization Ethics C. National Hospice and Palliative Care Organization (NHPCO) position statement and commentary on the use of palliative sedation in imminently dying terminally ill patients. J Pain Symptom Manage. 2010;39(5):914-923. Lo & Rubenfeld Palliative Sedation in Dying Patients JAMA. 2005;294:1810-1816 A “GOOD DEATH”

 Being treated as an individual, with dignity and respect  Being without pain and other symptoms  Being in familiar surroundings  Being in the company of close family and/or friends

 NHPCO “… means being physically comfortable, at peace in your own home, surrounded by your loved ones doing the things you love to do up until the very end.”

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