1. Medication Use at End of Life John Swegle, PharmD, BCPS Associate Professor (Clinical) University of Iowa College of Pharmacy Mercy Family Medicine Residency

2. “Keep them Comfortable” What does this mean? –Generally Calm/relaxed/comfortable Free of pain At peace –Don’t forget about the family/caregivers Hope is for a “good death”

3. General Goals Reduce suffering –Many involved with this Patient, family, healthcare provider Medications not always the answer –Spiritual issues Utilize spiritual care services –Social issues Utilize social workers

4. General Goals Focus on symptoms that are bothersome to the patient –Through conversations/observations Family wishes/perceptions –Make sure the patient is the focus of the conversation –Must have realistic goals All parties need to hear the same message

5. General Goals Avoid perception of giving up –Withdrawal of unnecessary medications/turning off devices is reasonable Focus is a transition of care away from a curative approach

6. General Goals Location of patient often dictates approach to care –Selection of medications –Route of administration –Aggressiveness of titration Need for reassessment –Access to healthcare professional

7. Communication Patients, families, caregivers What to expect What the medications are designed to do What is the plan from here going forward Education is involved in all these steps Be prepared to take time

8. Common Symptoms Encountered Pain Dyspnea Anxiety Nausea/vomiting Secretions Terminal restlessness Fatigue

9. Essential Drugs for End-of-Life Care Medications considered essential for comfort care in all settings (at least available for use): –Morphine (opioids) –Lorazepam (midazolam) –Haloperidol (other) –Antimuscarinic (atropine eye drops) Medications to consider: –Dexamethasone J Palliat Med 2013;16:38-43

10. Various Etiologies for Pain Physiologic –Approximately ¾ of patients entering the terminal phase will have pain requiring opioids Other types of pain –Emotional: Anxiety, depression, anger –Social: Interpersonal issues (family, loneliness, financial) –Spiritual: Non-acceptance, abandonment, paying for previous transgressions

11. General Opioid Rules Do not be fearful of them but treat them with respect There is not one agent that is better than another –Everyone responds differently –Selection takes into account other patient factors (age, renal function, other disease states, other medications, etc) Working with opioids is an art with some science behind it

12. Myths about Opioids Once someone goes on morphine, it means they will die –The intent of use is for comfort care –Provide for pain free periods –Often titrated/used on PRN basis Respiratory depression is a common side effect

13. Opioids Main uses in palliative care: –*Pain/comfort –*Shortness of breath –Overall comfort Potential benefits –Sedation –Calming effect –Improvement in quality of life

14. Opioid Selection Agents commonly used for end-of-life care: –Morphine –Hydromorphone –Fentanyl –Oxycodone Agents which are not ideal choices: –Meperidine –Any pill form –Any partial agonist or agonist/antagonist Am J Kidney Dis 2003:42:217-228 Drugs Aging 2007;24:761-776

15. Opioids Dosing: –Individualized and will need to be adjusted Some do poorly on 5 mg oral morphine Some require very high doses –Determine pain needs: ongoing coverage vs. PRN use Often dictated by setting PRN use is preferred at end-of-life however realize who will be administering the drugs

16. Initial Opioid Dosing IV/SQ –If using PCA, must determine if capable of pushing the button –Initial dosing Standard morphine PCA dose is 1-2 mg every 10-15 minutes PRN –If on basal/bolus – bolus dose is typically 50-100% of hourly basal rate Example: –Morphine 2 mg hourly infusion with 1 or 2 mg bolus every 15 minutes PRN

17. Initial Opioid Dosing PO/SL –Standard morphine dosing 2.5-5 mg MSIR every 1-2 hours PRN –Liquid morphine often used (Roxanol 20 mg/ml SL administration) If on basal/bolus – bolus dose is 10-15% of 24-hour dose Example: –Morphine sulfate 15-15-30 over 24 hours –Bolus is typically 5 mg every hour PRN

18. Opioid Comparison Dosing MedicationEquianalgesic dose (parenteral) Equianalgesic dose (oral) Fentanyl100mcg (single dose) 200 mcg (continuous dosing) 25 mcg/hr  SR morphine 65-90 mg per day Hydrocodone N/A30 Hydromorphone 1.57.5 Methadone Varies Morphine 1030 Oxycodone N/A20-30 Oxymorphone N/A10

19. Opioid Adverse Effects Constipation –Address and prevent CNS: sedation, confusion Nausea/vomiting Urinary retention Pruritis Respiratory depression Hyperalgesia Drugs Aging 2009;26(suppl 1):63-73 Canadian Family Physician 2007;53:426-427

20. Dyspnea Definition of dyspnea –Bad or difficult breathing Subjective symptom (similar to pain) –Many people are unable to relate to dyspnea –Unable to always correlate dyspnea with objective findings As with pain, focus more on what the patient tells you rather than what you or the family may observe

21. Dyspnea at End-Of-Life Focus on the symptom and not the sign Discuss treatment options with patient/family Most treatable causes of dyspnea have already been dealt with at this stage Routine use of oxygen near death is not supported by evidence (though some will use it) Attempt to reduce dyspnea by non-pharmacologic means (i.e. – fan at the bedside)

22. Dyspnea at End-Of-Life Common causes –Lung mets –Anxiety/panic –Secondary infection –Pulmonary edema –Metabolic acidosis secondary to multi-system failure –Newly developed pleural effusion –Anemia

23. Common Respiratory Medications Bronchodilators –Utilized in those with underlying pulmonary disorders Not always able to see objective improvement but the patient may claim to feel better –Oral/nebulized/IV all are available depending on which agent is selected Corticosteroids –Target inflammation –Dose appropriately and be aware of objective improvement versus “steroid effect” Semin Oncol 2011;38:450-459

24. Respiratory Depressants – Bezodiazepines Main agents to use: –Diazepam –Lorazepam Mechanism of action –Depression of hypoxic or hypercapnic ventilatory response –Alter the emotional response to dyspnea Avoid widespread use unless there is underlying anxiety J Palliat Med 2012;15:106-114

25. Respiratory Depressants – Opioids Morphine –Most frequently used opioid for treating dyspnea –Dosing/frequency similar to pain Order often written PRN pain/dyspnea –Not always useful for treating dyspnea Similar to the idea that not all pain should be treated with morphine Do not rely completely on opioids that the overall picture is ignored

26. Respiratory Depressants – Opioids Morphine: –Mechanism of action (multiple theories) Shifting of central PCO 2 perception –Resetting of the homeostatic control of PCO 2 –Will allow the body to tolerate higher levels of CO 2 without feeling respiratory fatigue Preload reduction Relaxation effect? Miscellaneous mechanisms Am J Respir Crit Care Med 2011;184:867-869

27. Anxiety Culmination of physical and psychological symptoms mixed in with the reality of the situation –Psychological factors (i.e. – fears of isolation, factors associated with death) may impact the physical findings Presents in many ways –Restlessness, insomnia, hyperactivity, jitteriness, apprehension, worry

28. Management of Anxiety Attempt to identify the etiology –Example: anxiety secondary to dyspnea, delirium –Drug-induced or drug withdrawal –The relative from California Consider non-pharmacologic solutions –Other disciplines: social worker, spiritual care –Family support –Psychological support Curr Opin Support Palliat Care 2007;1:50-56

29. Management of Anxiety General medications used: –Benzodiazepines Lorazepam 0.5-1 mg hourly PRN Clonazepam (similar dosing) –Antipsychotics Haloperidol 0.5-2 mg hourly PRN Quetiapine 12.5-25 mg every 2 hours PRN –Antidepressants Curr Opin Support Palliat Care 2007;1:50-56

30. Nausea Entirely subjective experience –Sensation which typically precedes vomiting Epidemiology is uncertain due to methodological challenges –Heterogeneity of patient populations, various study settings, etc. Fair to say that the symptom is very disturbing Clin Interv Aging 2011;6:243-259

31. Nausea Similar to many symptoms, it’s best to try and identify the etiology –Or at least identify the receptors you wish to target –Not always possible (multiple causes may be involved) Areas of involvement –Chemoreceptor trigger zone –Labyrinths –Peripheral afferents Do not forget the bowels

32. Antihistaminic Agents for Nausea Selected MedicationsComments Diphenhydramine (Benadryl  )Useful agent but sedating Dimenhydrinate (Dramamine  )Often used for “motion sickness” Meclizine (Bovine , Antivert  )Often prescribed for “dizziness” Promethazine (Phenergan  )Predominately an antihistamine but has small amount of dopamine blocking properties

33. Medications for Nausea Dopamine receptor antagonists –Work by blocking dopamine 2 (D 2 ) receptors –Useful group of medications for nausea Often used as first-line for generalized nausea –Adverse effects may be limiting factor Dystonic reactions, akathesia, sedation

34. Dopamine Receptor Antagonists Selected MedicationsComments Prochlorperazine (Compazine  ) Generic dopamine blocker and preferred agent to use in many acute situations; Less sedating than promethazine Haloperidol (Haldol  ) 0.5-1 mg PO/0.5 mg SQ/IV every 6-8 hours (may be more frequent administration) Baggage associated with use; newer antipsychotics also used but tend to be more expensive Metoclopramide (Reglan  )Dual mechanism: blockade of dopamine receptors and prokinetic agent on GI tract

35. Medications for Nausea Serotonin antagonists (i.e. – ondansetron) –Block serotonin (5-HT 3 ) receptors through blockade of local receptors in the GI tract (primary) and will block serotonin receptors centrally (secondary) –Key concept….. These agents are very useful for emetogenc causes which are associated with release of serotonin

36. Secretions Often distressing to caregivers/family Precise mechanism unclear –Generally referred to as inability to clear secretions –Air flowing over secretions with respiration creates the noise The “death rattle” –Associated with death being near

37. Secretions – Management Education of family Non-pharmacologic –Repositioning –Suctioning Often short-lived benefit and may be more distressing to family Am J Health Syst Pharm 2009;66:458-464

38. Secretions – Management Medications: –Atropine 1% eye drops; 1-2 drops po hourly PRN 0.4 mg SQ/IV q4-6 hours PRN –Glycopyrrolate 1-2 mg po BID-TID 0.1-0.2 mg SQ/IV every 4-8 hours PRN –Scopolamine –Octreotide

39. CNS - Fatigue Numerous causes –Pain, medications, deconditioning, anemia, cytokine release, metabolic abnormalities, depression, infection, dehydration –Increased sleep is an expected outcome as end of life gets closer Is there a need to treat? –Is it a primary concern to the patient? –Are there reasonable options that minimize risks?

40. Terminal Restlessness This is a one hour talk Generally defined as unsettling behaviors in the last few days of life General approach: –Look for underlying cause –Remove or treat cause if possible (i.e. – drugs) –Create safe environment for all parties –Maintain patient dignity

41. Terminal Restlessness Non-pharmacologic –Comfortable environment (i.e. – music) –Familiar home objects –Involve family members –Limit room/staff change –Limit interruptions (i.e. – blood draws) –Reorienting by family or staff

42. Terminal Restlessness Pharmacologic –Haloperidol usual agent of choice 0.5-1 mg every 1-2 hours PRN –Lorazepam typically second line 0.5-2 mg hourly PRN –Often will see combinations of these two agents used

43. Other Symptoms Encountered Depression Behavioral problems Anorexia Insomnia Family crisis situations

44. Discontinuing Medications If actively dying, stop everything but comfort meds And stop the monitoring…..

45. Concluding Remarks Be realistic in your expectations from drugs –Not everyone responds the same way Include the patient in the discussion More expensive medications are not always better Don’t wait to treat the symptoms

46. Questions?