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

Robert G. Wahler, Jr., Pharm.D., BCGP, FASCP, CPEClinical Assistant Professor, UB SPPSDirector, Clinical Pharmacy Services, Niagara Hospice

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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.

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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 delirium.

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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 palliative care 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

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.

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SELF-ASSESSMENT QUESTION Which common LTC admission diagnosis is the highest

ranked reason for hospice admission?A. CancerB. Heart FailureC. DementiaD. COPDE. Cerebrovascular Disease

Conditions qualifying for hospice admission Conditions requiring palliation

RankReported principal diagnosis Count Percentage1 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%

TABLE 2—THE TOP TWENTY PRINCIPAL HOSPICE DIAGNOSES, FY 2017(SIMPLIFIED)

CHANGES DURING THE DYING PROCESS

Change Manifested by/Signs of:Fatigue, weakness Decreasing function, hygiene

Inability to move around bedInability to lift head off pillow

Cutaneous ischemia Erythema over bony prominencesSkin breakdown, wounds

Decreasing appetite/food intake, wasting

AnorexiaPoor intakeWeight loss, muscle and fat, notable in temples

Medscape Internal Medicine 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)

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CHANGES DURING THE DYING PROCESSChange Manifested by/Signs of:Cardiac dysfunction, renal failure

TachycardiaHypertension followed by hypotensionPeripheral coolingPeripheral and central cyanosis (bluish color of extremities)Mottling of the skin (livedoreticularis)Venous pooling along dependent skin surfacesDark urineOliguria, anuria

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CHANGES DURING THE DYING PROCESSChange Manifested by/Signs of:Neurologic dysfunction, including:Decreasing level of consciousness

Increasing drowsinessDifficulty awakeningUnresponsive to verbal or tactile stimuli

Decreasing ability to communicate

Difficulty finding wordsMonosyllabic words, short sentencesDelayed or inappropriate responsesVerbally unresponsive

Terminal delirium Day-night reversalConfusionAgitation, restlessnessPurposeless, repetitious movementsMoaning, groaning

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CHANGES DURING THE DYING PROCESSChange Manifested by/Signs of:Respiratory dysfunction

Change in respiratory rate—increasing first, then slowingDecreasing tidal volumeAbnormal breathing patterns—apnea, Cheyne-Stokes respirations, agonalbreaths

Loss of ability to swallow(Opportunity for Pharmacists to “shine”)

DysphagiaCoughing, choking, aspirationLoss of gag reflexBuildup of oral and tracheal secretionsGurgling (“death rattle”) 12

CHANGES DURING THE DYING PROCESSChange Manifested by/Signs of:Loss of sphincter control

Incontinence of urine or bowelsMaceration of skinPerineal candidiasis

Pain Facial grimacingMoaningTension in forehead, between eyebrows

Loss of ability to close eyes

Eyelids not closedWhites of eyes showing (with or without pupils visible)

Rare, unexpected events:Bursts of energy just before death occurs, the "golden glow"Aspiration, asphyxiation

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TWO ROADS TO DEATH

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Normal

The Usual Road

The Difficult Road

Dead

Sleepy

Lethargic

Obtunded

Semicomatose

Comatose

Restless

Confused Tremulous

Hallucinations

Mumbling delirium

Myoclonic jerks

Seizures

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 (http://www.medscape.com/viewarticle/716463_2 Accessed 4-2-15)

Anxiety

Dyspnea

Pain

Nausea/Vomiting

“Gurgling”

PORTMANTEAU – DESIRABLE PROPERTIES1. Multiple therapeutic effects2. Minimal drug interactions3. Multiple routes of administration4. Wide therapeutic window5. Cost-effective6. Convenient dosing schedule7. 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

Lorazepam 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 Medicines 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 FORADULTS

• “… 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”*

European Palliative Care Research Centre TVT trial https://www.ntnu.edu/prc/tvt-study-information Accessed 4-1-2017

• Two Step Versus the Standard Three Step Approach of the WHO Analgesic Ladder for Cancer Pain Relief trial • Remove Step 2? World Health Organization

http://www.who.int/cancer/palliative/painladder/en/Accessed 4-1-2017

*Nersesyan, H., & Slavin, K. V. (2007). Therapeutics and Clinical Risk Management, 3(3), 381–400. X

WHERE TO START Base the initial treatment on the severity of pain the

patient reports. Mild – Non-opioid 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, APSClinical Practice Guidelines Series, No. 3. Glenview, IL: American Pain Society.

1919Whitten, et al. The Permanente Journal 2005;9(4):9-18.

The Dosing Frequency Conundrum

3 hrs

2.5 hrs

Suffering

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, APSClinical 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 opioids 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 PAINNSAIDs & Cox-2-Inh • Pros

• Useful for mild to moderate pain

• Adjunctive• Cons

• Ceiling effect• Toxicity (esp. elderly)

• GI• Renal• Cardiac

Corticosteroids• Anti-inflammatory

• Start dexamethasone 2-16mg/day (PO or IV)

• Up to ~30mg daily• Anti-emetic• Appetite stimulation• Antidepressant effects -

“stimulatory” • Significant long-term

side effects (mitigated)

OPIOID ROUTES OF ADMINISTRATIONNon-Parenteral• PO/SL/Transbuccal• Inhaled• Intranasal • Rectal• Topical

Parenteral• IM• IV

• Continuous infusion*• Sub-Q site

• 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 ANDChlorpromazine orDiazepam orMidazolam

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DYSPNEA - OPIOIDS Help relieve sensation of shortness of breath 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

relax. Step 1– non-pharm Step 2– short-term

Lorazepam Alprazolam Amitriptyline (w/

depression) Step 2- long-term

Buspirone SSRI

Escitalopram (Lexapro)

Sertraline (Zoloft) Mirtazepine (w/

depression, insomnia and anorexia)

Disorientation, hallucinations, aggressive

Step 1 Haloperidol

Step 2 Haloperidol + lorazepam

(sedation required) Step 3

Haloperidol + Midazolam(Versed) or chlorpromazine (Thorazine)

Agitation in terminal stages 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.” 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

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NAUSEA AND VOMITING

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Gut wall Gastric irritants Abdominal radiotherapy Intestinal distention Cytotoxic chemo

Treatments Step 1

H2 antagonistProton-Pump Inhibitor

Step2Metoclopramide

Step 3Ondansetron (Zofran)

Area postrema Morphine, digoxin Hypercalcemia/ uremia Clonidine Cytotoxic chemo

Treatments Step 1

HaloperidolMetoclopramide

Step 2Step 1 + dexamethasone

pamidronate(Aredia)for hypercalcemia

Step 3Ondansetron +

dexamethasone

NAUSEA AND VOMITING

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Cerebral cortex Fear/anxiety Raised intracranial

pressure Hyponatremia

Cerebral cortex Step 1

Dexamethsone Step 2

AmitriptylineHaloperidolLorazepam

Step 3Limited free water ±3% saline ±haloperidol

Vestibular nuclei Movement Vertigo

Vestibular nuclei Step 1

Diphenhydramine (Benadryl)

Dimenhydrinate(Dramamine)

Step 2Meclizine (Antivert) or

Cyclizine (Marezine) Step 3

Glycopyrrolate(Robinul)

Scopolamine

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. 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.

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TERMINAL SECRETIONS - Gurgling, “death rattle” Atropine 1% ophth gtts SL 2-3 q2-3 h PRN

Not earlier – dry mouth Also

Scopolamine patch Glycopyrrolate

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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)

Kirk TW, Mahon MM, Palliative Sedation Task Force of the National H, Palliative Care Organization Ethics C. National Hospice andPalliative 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

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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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