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Pharmacological Interventions for Symptom Management at End-of- Life

Pharmacological Interventions for Symptom Management at End-of- Life. Rebecca Weber MSN, APRN, NP-C, ACHPN. Disclosure. There are no relevant financial interests or conflicts of interest that have been disclosed by this presenter. Agenda. Palliative Care vs Hospice definition

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Pharmacological Interventions for Symptom Management at End-of- Life

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  1. Pharmacological Interventions for Symptom Management at End-of- Life Rebecca Weber MSN, APRN, NP-C, ACHPN

  2. Disclosure • There are no relevant financial interests or conflicts of interest that have been disclosed by this presenter.

  3. Agenda Palliative Care vs Hospice definition Leading causes of Death in U.S Disease trajectory of chronic disease Frequent Symptoms associated with imminent death Pharmacological Treatment of these symptoms

  4. Objectives • Identify the four most frequently associated symptoms associated with imminent death • Recognize the best pharmacological interventions to use to alleviate symptoms as part of end-of-life care • Differentiate the pharmacological intervention to use for anxiety vs agitation

  5. Palliative care vs Hospice Palliative Care • Provide comfort at the same time they receive curative treatment • Paid by insurance or self pay • Any stage of disease • Typically happens in hospital (at this time) • Involves patient and family • Focus: Goals of Care, Advanced Directives, Disease trajectory, Symptom management • Dying cares (if can’t discharge to hospice) • Hospice • Provide comfort after curative treatment has stopped and Prognosis 6 months or less • Paid by Medicare, Medicaid or Insurance • Services usually provided at place they call home (own residence, nursing home, assisted living or in a Designated Hospice house • Involves patient and family • Focus: Physical, emotional and spiritual needs. Symptom management and dying care

  6. Palliative Care and Hospice (cont.)Life Limiting Illness • Cancer • Heart disease • Respiratory Disease • Alzheimer’s/Dementia • Stroke/Coma • Neurological Disease • Renal Failure • Liver Disease • General (non specific terminal illness with rapid decline)

  7. Disease Trajectory

  8. Symptom Clusters by Diagnosis • End Stage Heart Failure • Dyspnea (from Fluid retention), Fatigue, Depression, Anxiety & Insomnia (Solono & Gomes (2006). • Pain (25% with Moderate to Severe-site variable), Nausea, Constipation • More deaths than any other disease, more symptoms than cancer • Cancer • Pain. Nausea and vomiting: Anxiety and depression, wound care and confusion. Weak, tired and assistance with ADLs (Stiel and Dominik, 2014) • COPD • Cough, Dyspnea (Air Hunger) and Fatigue • Dementia • Depression, Anxiety , Delusions, Hallucinations, Delirium, Pain

  9. Advanced Organ Dysfunction • Hepatic Failure • All Opioids metabolized by the liver • Smaller Doses and longer dosing intervals my be appropriate • Sublingual meds will help with first pass metabolism • Renal Failure • Most opioids are excreted renally • Standard of care-avoid morphine • Drugs of choice-methadone, fentanyl • Delirium • Treat with antipsychotics and pain medication

  10. When I die, I want to die in my sleep, so I practice by taking a lot of naps!

  11. Frequent Symptoms Associated with Imminent Death • Dyspnea (56.7%) • Pain (52.4%) • Terminal Secretions (51.4%) • Confusion (50.10%) • Symptoms in the last 2 weeks of life (Kehl & Kowalkowski, 2013)

  12. Dyspnea

  13. Dyspnea Definition: subjective sensation of difficult breathing Common Finding in: Cancer, CHF (3rd most prevalent symptom),COPD (most prevalent symptom) and AIDS • In a study of those with advanced AIDS, COPD, CHF, advanced cancer, and renal disease,50% of individuals experienced dyspnea. • -Dyspnea is often associated with fatigue, sleep, anxiety and depression. Solono & Gomes (2006) • In studies, those with COPD had higher levels of breathlessness over time, whereas those with lung cancer experienced worsening dyspnea toward the end-of-life. Bausewein & Booth (2010)

  14. Dyspnea Goals of Rx Goal of Treatment: 1. Focus on treating or ameliorating the underlying cause (when possible) Example: Obstructing tumors, pulmonary embolism, pleural effusions, infections, heart failure, abdominal ascites, superior vena cava syndrome 2. Optimize Pharmacological Management to relieve suffering. Oral or parenteral opioids remain the standard initial therapy Kamal & Maquire, 2011

  15. Oxygen for Dyspnea • Supplemental O2 can provide relief for patients who are hypoxemic at rest or during minimal activity • Monitor effectiveness by patients subjective report as there is no correlation between respiratory rate and/or oxygen saturation levels and comfort • Most patients find Nasal cannula more comfortable than facial mask Phillip, 2006: Weissman (2005) • Pearls • Humidify Oxygen for comfort • Remove O2 Sat monitor so family focuses on patient and not machine • At home, a fan on the face gives subjective relief

  16. Opioids/Dyspnea • Opioids are the medication of first choice for relieving symptoms of Dyspnea • Opioids should be dosed and titrated for the individual patient with consideration of multiple factors for relief of dyspnea (renal, hepatic, pulmonary function, Opioid hx) • Mechanism of Action: • Reduce dyspnea by decreasing the respiratory drive • Alter responses to hypoxia and hypercapnia • Changes in Bronchoconstriction • Alleviate feelings of air hunger and anxiety

  17. Opioids are underused for Dyspnea • Respiratory depression is a widely held concern with the use of Opioids for the relief of dyspnea Mahler et al. CHEST 2010 • Results from studies of patients with COPD, Cancer, or Heart failure, evaluating the use of opioids for dyspnea failed to demonstrate a relationship between opioids and Respiratory Compromise. • Study showed with proper titration, opioids can relieve dyspnea by decreasing respiratory rate while avoiding iatrogenic hypercapnia or hypoxia (and thru changes in bronchoconstriction). There was a decrease in respiratory rate and improvement in dyspnea with titration of morphine or hydromorphone with no significant changes in respiratory parameters indicating no opioid induced respiratory depression. • Clemens & Quednau, 2007; Gomuttbutra & O’Riordan (2012); Horton 2013

  18. Opioid Studies on Dyspnea cont. • This prospective, non randomized study assessed the effect of opioid treatment on ventilation in 11 dyspneic palliative care patients with strong opioids. The assessments measured changes in peripheral arterial oxygen saturation (Sa02),transcutaneous arterial pressure of PCO2, RR and Pulse rate during the titration phase with morphine or hydromorphone. The aims of the study were to verify the efficacy opioids for the management of dyspnea. The Opioid produced significant improvement in the intensity of dyspnea (P= 0.003), RR decreased from 42 to 35 per min after 1st opioid administration, and after 90 min, decreased to 25 min. There was no opioid induced respiratory depression. • Clemens & Klschik, 2006

  19. The Principle of Double Effect • Although there may be a concern that Opioids and Benzodiazepines may hasten death, the principle of the double effect justifies their use to relieve dyspnea at the end-of-life • This principle differentiates between providing analgesic medication with the INTENT to relieve symptoms that might inadvertently hasten death vs providing medication to INTENTIONALLY cause death

  20. Equianalgesic Table

  21. American Thoracic Society Guidelines for the Treatment of Dyspnea • Moderate Dyspnea • Treat underlying disease • Treat psychosocial factors • Pulmonary Rehabilitation • Consider Anxiolytic • Severe Dyspnea • Treat underlying disease • Treat psychosocial factors • Pulmonary Rehabilitation • Facial cooling (fan) • Anxiolytic • Opioids • Noninvasive ventilation

  22. STARTING DOSAGES OF OPIOIDS AND THEIR DURATION OF EFFECT IN OPIOID-NAIVE PATIENTS WITH MODERATE TO SEVERE PAIN OR DYSPNEA*(American Thoracic Society)ATS • These dosing recommendations do not apply to patients who have previously used opioids because dosages for such patients will be higher and must be individualized. The correct dose and interval for opioid administration in all patients are those that relieve dyspnea or pain without intolerable adverse effects. There is no upper limit—that is, the dose should be increased as needed to produce the desired effect or until intolerable side effects occur. Reassessment of the drug's effects on the patient and titration of the opioid are the mainstays of successful management.

  23. Morphine Sulfate/Dyspnea • Morphine sulfate is the best studied • Potential Side Effect: Respiratory suppression but careful titration of dose to patient symptoms helps avoid this. Histamine release • Generally recommended due to: • Low cost, Efficacious • Familiarity to the health care team • Morphine 10mg IV = 30 mg PO • There is no “ceiling” for dosing opioids

  24. Morphine Sulfate/DyspneaInpatient Palliative Care example • Morphine 10mg/0.5 ml SL q 4 hours scheduled to keep RR<24 • Morphine injection 2-4 mg IV q 15 min PRN • Morphine 10mg/0.5 ml concentration Give 10-20 mg q 1 hour PRN • Morphine SR 10-20 mg daily in divided doses, with active evaluation and gradual titration ot desired effect. (Abernethy et al (2003)

  25. Morphine Sulfate/DyspneaHospice example • Available in Liquid, tablets, solutabs • For Moderate/Severe Pain or Dyspnea (goal: keep RR <24 min) • Morphine Sulfate 20mg/ml • Take 0.25 to 0.5 ml (5 mg to 10mg) PO/Sublingal every 2 h PRN • Morphine IR 15 mg tablets • Take ½ to one tablet (l7.5 mg to 15 mg) q 2 h PRN • Morphine Sulfate solutabs 2.5 mg to 5 mg tabs • 5 mg tabs: Take 1-2 tabs (5 mg to 10mg) PO/SL q 2 hr PRN • 2.5 mg tabs (take 1-2 tabs (2.5 to 5 mg) PO/SL q 2 hr PRN

  26. Morphine Contraindications • Morphine has a high risk of urticarial or pruritus secondary to histamine release or toxicity manifested as myoclonus, especially in the setting of Renal failure • Metabolism: • Metabolized in liver, renally excreted • Do not use if GFR is < 30ml/min (or Cr >1.2) due to rapid accumulation of active, non dialyzable metabolites (M3-M6 gluconoride)that are neurotoxic.

  27. Opioid induced Myoclonus(treat with Clonazepam 0.5 mg TID up to 20mg/day or Ativan 0.5-2.0 mg q 4h)consider Methadone or Fentanyl

  28. Hydromorphone/DyspneaHydromorphone 1.5 mg IV =7.5 mg PO(4-7 times more potent than morphine) • Palliative Care Example • Hydromorphone 0.5-1 mg IV q 3 hours PRN • Hydromorphone (Dilaudid) • Supplied in 2-4 mg tabs • Take1 to 2 mg q 4 hours PRN • Hospice example • Hydromorphone 10 mg/ml liquid • Take 0.1 ml to 0.2 ml (1-2 mg) PO/SL q 2 h

  29. Oxycodone/Dyspnea • Dyspnea is a common symptom in patients with advanced cancer. Systemic morphine administration has been reported a an effective pharmacological treatment to control dyspnea. To evaluated the effect of controlled-release oxycodone on the relief of dyspnea, we investigated 3 cases with opioid substitution from SQ morphine to oral oxycodone. In all cases, both opioids provided equivalent effects for the palliation for cancer dyspnea with no significant adverse effects. • Shingo & Okada 2006

  30. Oxycodone/DyspneaOxycodone 20mg = Morphine 30 mg • 1.5 times more potent than morphine • Roxicodone 20mg/ml concentrated • 5-10 mg q 3-4 hours PRN or scheduled to keep RR <24 • Oxycodone is not available in IV

  31. Benzodiazepines Anxiety related Dyspnea • Treats the affective response from Dyspnea • In a prospective, non randomized study of hospitalized patients with cancer, combined use of lorazepam and opioids (morphine and Hydromorphone) demonstrated a significant reduction in dyspnea without any increased respiratory depression. • Clemens & Klaschik, 2011. • In a retrospective review of hospitalized patients receiving palliative care, those who received benzodiazepines and opioids had better relief from dyspnea than those receiving only opioids • Gomutbutra& O'Riordan, 2013

  32. Benzodiazepines for Dyspnea cont. • Patients with anxiety disorders more frequently report dyspnea, patients reports of dyspnea usually cluster with the presence of anxiety or depression, and treating anxiety/depression may thus help ameliorate dyspnea. SSRI’s may have a direct effect of centers that control the perception of breathlessness. • Kamal & Maquire (2012) • Lorazepam (Ativan) • If Anxiety is major contributor to the Dyspnea • Lorazepam 0.5 to 1.0 mg every hour until symptom is controlled, with routine dosing q 4-6 hours thereafter

  33. Corticosteroids for Dyspnea • Indicated for: • COPD • Asthma • SVC Syndrome • Lymphangitis

  34. Palliative Ventilator Withdrawal Pharmaceutical Management • Opioids (Morphine: 2-4 mg IV q 15 m or Hydromorphone 0.2-0.4 IV q 15 m, or Fentanyl (25-50mcg IV q 10 min) • Benzodiazepines : Lorazepam (0.5 mg-1mg IV q 1h PRN) or • Midazolam 1-2 mg IV q 1 h PRN • given for symptoms of RR >30 (or double of baseline). Sustained Facial grimace, sustained motor movement of posturing, Retractions (intercostal or abdominal), respiratory distress • Antipsychotics: If symptoms cause distress (Hallucinations/Agitation) • Haldol 0.5 mg IV q 1 hour PRN • Anticholinergics : atropine 1% eye drops Sl q 4 h PRN

  35. PAIN

  36. Pain Management at End of Life • Goal: • Pain relief: Balance of analgesia, increased function, and safety. • For the actively dying, scale tips towards analgesia, less emphasis on function • Long term survivor: Goal is enhanced function over complete pain control

  37. Pharmacologic Management of Pain • Pain can stem from many causes, including chronic conditions, such treatments as chemotherapy-related neuropathies, and disease progression. • Significant pain calls for aggressive pain management, including both pharmacologic and non-pharmacologic. The focus today will be pharmacologic.

  38. Pain Categories • Somatic Pain (cutaneous or deep tissue): usually managed with non-opioids and opioids • Neuropathic pain: treated with adjuvant analgesics and opioids if little or no response to non-opioids • Visceral Pain:(due to infiltration, compression or stretching) Controlled by opioids and corticosteroids

  39. Cancer Pain • Tumor-Related Pain Syndromes • Bone metastases • Hepatic capsule distention due to Metastases • Plexus involvement by tumor • Chemotherapy induced peripheral neuropathy • Osteonecrosis from corticosteroids • Radiation Related Pain Syndromes • Chest tightness, Fistula formation, Myelopathy, Osteoradionecrosis, peripheral never entrapment, plexopathies

  40. World Health Association (WHO) Ladder • Mild (1-3 intensity) • Acetaminophen, non-steroidal anti-inflammatory drugs, adjuvant meds such a tricyclic antidepressants and muscle relaxants • Mod (4-6 intensity) • Combo opioids + adjuvant drugs • Severe (7-10) • Opioids (morphine, hydromorphone, plus adjuvant drugs

  41. Pharmacologic Management of Pain Opioids Nociceptive and Neuropathic pain Immediate Release: Faster onset Controlled Release: more constant control of pain, less chasing pain Tramadol Weak opioid agonist and a serotonin-norepinephrine reuptake inhibitor, thus a ceiling dose of 300mg/day avoid in patients with seizure risk or suicidal ideation SE: Dizziness -Non Opioids • Acetaminophen • Analgesic and antipyretic • (no more that 3000 mg per day) • Caution: Altered Hepatic Function or excessive ETOH intake • NSAIDS • Analgesic and antipyretic and anti inflammatory • Indication: Nociceptive or musculoskeletal pain syndromes • Caution: GI Bleed, Renal dysfunction, platelet aggregation abnormalities

  42. Morphine for Pain • Gold standard: low cost, efficacy, familiarity to the health care team • Used for Equianalgesic dosing for other opioids • Indications: Pain (or respiratory distress) • Usual route of delivery for EOL • IV (in patient, not hospice (community based) • PO • SL (Liquid gtts often used in Hospital setting, solutabs in Hospice)

  43. Opioid Prescribing Guidelines American Pain Society

  44. Morphine IR • MSIR • Onset (O) and Duration (D) • Oral IV • O: 30-60 min O: 5 -10 min • D: 3-6 hours D: 3-6 hours _________________________________ • Starting Dose • 15-30 mg 2-10 mg • Q2-4 h q 2-4 hours • MSIR • Approximate Equianalgesic dose • Oral IV • 30 mg 10 mg

  45. HydromorphoneOral: Hydromorphone = 30 mg Morphine • Dilaudid • Onset (O) and Duration (D) • Oral IV • O: 15-30 min O: 15 min • D: 4-6 hours D: 4-6 hours • Starting Dose • 2-4 mg 0.5-2 mg • Q4 h q 2-4 hours • Approximate Equianalgesic dose • Oral IV • 7.5 mg 1.5 mg • Better choice for hepatic impairment than Morphine • The analgesic potency of Hydropmorphone is roughly 5 times that of morphine

  46. Methadone • Methadone • NMDA Antagonist, inhibits norepinephrine and serotonin reuptake • Good for Bone Pain, neuropathic pain, renal disease • Long 1/2 life up to 190 hours: Do not use as PRN • Dose: 5 mg po 2-3 times daily • Onset 30-60 min Duration >8 h • Caution: QTc, baseline EKG, and subsequent EKG if titrating >100mg/day or unexplained syncope or seizure like symptoms.DC of QTc > 500 ms

  47. Adjuvant MedicationsNeuropathic pain • Antidepressant: • SNRI • Nortriptyline, Venlafaxine (Effexor XR), Duloxetine (Cymbalta) • Antiepilepsy drugs • -Gabapentin, Pregabalin (Lyrica) • Other • Ketamine for pain refractory to opioids or intractable side effects from opioids, esp if the pain is neuropathic in nature or a high degree of morphine tolerance is suspected.' • Ketamine is an N-Methyl-d-aspartate receptor (NMDA) agent that may be opioid • Lidocaine Patch 5%

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