Opioids in Serious Medical Illness

Transcription

1 Opioids in Serious Medical Illness Jacob J. Strand, M.D. Assistant Professor of Medicine Medical Director, Palliative Care Clinical Services Mayo Clinic Mayo Clinic Opioid Conference 2013 MFMER slide-1

2 DISCLOSURE Speaker (Dr. J.J.Strand) Relevant Financial Relationship(s) None related to this talk Off Label Use Opioids for dyspnea 2013 MFMER slide-2

3 Objectives Choose safe prescribing options for opioids in the treatment of non-pain symptoms. Develop a step-wise approach to the use of opioids in patients with liver & renal failure Prevent avoidable side effects in patients with a serious illness who are being treated with opioids MFMER slide-3

4 Case 1 A 62-year-old male, with a complex past medical history including chronic myofascial low back pain, diabetes mellitus and severe chronic obstructive pulmonary disease on 4L home oxygen therapy presents to your outpatient clinic with ongoing severe dyspnea on exertion. He has struggled with repeated hospitalizations for his dyspnea and is now unable to play with his grandchildren due to the dyspnea of this minimal exertion. While reasonably comfortable at rest, he develops increasing dyspnea ambulating in your office, describing an inability to catch my breath associated with anxiety MFMER slide-4

5 Case 1 Afterwards, he is visibly tachypneic and using accessory muscles of respiration. Vitals signs reveal a temperature of 37.9, respiratory rate of 32, heart rate of 104 and pulse oximetry at 93% on 4L/min of oxygen by nasal cannula. Pulmonary examination exhibits a prolonged expiratory phase and intermittent scattered rhonchi throughout his lung fields, with hyperresonance to percussion. Jugular venous pressure is measured at 6cm of water at 45 degree bed angle MFMER slide-5

6 Which one of the following interventions is most appropriate to treat her dyspnea? A. Start fentanyl 25 micrograms with 2mL saline via home nebulizer four times daily as needed B. Start lorazepam 0.25mg PO BID as needed for dyspnea C. Increase his home oral furosemide D. Start oxycodone 2.5mg PO q4hrs as needed for dyspnea E. Increase oxygen by nasal cannula to 5 liters/minute 2013 MFMER slide-6

7 Answer D. Start oxycodone 2.5mg PO q4hrs as needed for dyspnea MFMER slide-7

8 Dyspnea Complex, uncomfortable sensation that includes air hunger, increased effort or work of breathing, and chest tightness Self report is the gold standard for assessment Use 0-10 scale Neural structures involved in pain and dyspnea may be shared Nishino T. Br J Anaesth. 2011;106(4): Campbell ML. AACN Adv Crit Care. 2011;22(3): MFMER slide-8

9 BONUS PEARL: Non-pharmacologic strategies for Dyspnea Proper positioning & pursed-lip breathing Gait aids (e.g. walkers) Fans: RCT in refractory dyspnea After 5 minutes with handheld fan, statistically significant decrease in breathlessness Guided meditation/relaxation training Acupuncture Oxygen? Galbraith S et al. J Pain Symptom Manage. 2010;39(5): Greer JA et al., J Pain Symptom Manage Jul 10. [epub ahead of print] Abernethy et al., Lancet Sep 4;376(9743): MFMER slide-9

10 Opioids Are First Line Pharmacotherapy Improve subjective sensations of dyspnea and are safe when dosed appropriately for properly selected patients. Class effect: No data to support morphine as superior to other opioids Parshall MB et al., Am J Respir Crit Care Med Feb 15;185(4): Coyne PJ et al. J Pain Symptom Manage. 2002;23(2): MFMER slide-10

11 Opioids for Dyspnea Starting doses In an opioid-naïve patient: Morphine 5 to 7.5 mg PO every 4 hours Oxycodone 2.5 to 5 mg PO every 4 hours Hydromorphone 1 to 2 mg PO every 3 hors Long acting opioids: Class effect Increase no more frequently than every week Good data in Morphine SR 10-20mg PO qam Abernathy AP et al. BMJ. 2003;327(7414): Currow DC et al., J Palliat Med Aug;16(8): MFMER slide-11

12 Management of Dyspnea Inhaled opioids no more beneficial than placebo in controlled trials. Appropriately dosed opioids should NOT cause respiratory depression MFMER slide-12

13 Take Home Points In patients with severe dyspnea, appropriately dosed opioids are first-line therapy for symptomatic relief MFMER slide-13

14 Case 2 BL is a 67yoM with a past medical history of diabetes mellitus & end-stage renal disease on hemodialysis for the past 4 years with recently diagnosed cirrhosis, secondary to previous alcohol use (now sober x10yrs). He also carries a diagnosis of metastatic prostate adenocarcinoma with diffuse spinal metastases, but his disease is currently stable on androgen deprivation therapy. He presents for follow-up in your outpatient practice for increasing back pain. He describes the pain as a deep aching sensation in his low-back with painful burning in his buttocks & thighs bilaterally MFMER slide-14

15 Case 2 Imaging shows no evidence of malignant spinal cord compression. He does have evidence of some nonmalignant spinal stenosis levels L3-L5. Of note, he has not responded to previous attempts at epidural steroid injections tried at numerous juncture in the past. The pain affects his ability to walk & perform most ADLs. He has been tried on a number of analgesics including acetaminophen, up to 3grams/day, gabapentin which caused confusion & morphine which made him too sleepy MFMER slide-15

16 What is the next best option for managing this patient s pain? A. Tramadol 50mg PO q6hrs prn pain B. Hydromorphone 2mg PO q4hrs prn pain C. Ibuprofen 600mg PO q8hrs prn pain D. Fentanyl patch 25mcg/hr changed every 72hrs E. Oxycodone 7.5mg PO q4hrs prn pain 2013 MFMER slide-16

17 Answer B. Hydromorphone 2mg PO q4hrs prn pain 2013 MFMER slide-17

18 The right dose is the dose that provides adequate pain relief with acceptable side effects MFMER slide-18

19 There is a Tension Between Safety and Appropriate Analgesia Patients Report Inadequate Analgesia as Persistent Fear Present in most serious illnesses. Over 1/3 of patients with cancer do not receive analgesia according to their need. Pain impairs quality of life and function which can adversely affect survival. Greco MT et al., J Clin Oncol Dec 20;32(36): MFMER slide-19

20 In patients with serious illness nonopioid adjuvants often carry their own safety concerns. And, there are safe ways to use opioids in these patients MFMER slide-20

21 Renal Failure & Opioids Toxic metabolites accumulate Morphine Hydromorphone Increased ½ life of many drugs Tramadol Oxycodone Variability in ability to dialyze opioids Methadone & fentanyl = no Morphine & tramadol = yes King S et al., Palliat Med Jul;25(5): Dean M., J Pain Symptom Manage Nov;28(5): MFMER slide-21

22 Cirrhosis & Opioids Protein Bound Opioid Free Drug Metabolic pathways Clearance of metabolites Increased drug ½ life Variable onset of analgesia Increased effect in heavily protein bound drugs Increased generation of toxic metabolites. Chandok N & Watt KD. Mayo Clin Proc May;85(5): Dwyer JP et al., J Gastroenterol Hepatol. 2014;29(7): MFMER slide-22

23 Opioid Protein Binding Metabolism Morphine Mod/high Liver (glucuronidation) bioavailable w/liver failure & toxic metabolites Hydrocodone Low Liver CYP2D6 time to onset in liver failure Pearl 1. Avoid in Renal failure 2. Avoid in hepatic failure or cirrhosis 1. Variable efficacy; combination w/acetaminophen limits use. Oxycodone Mod/high Liver CYP 2D6/3A4 Half life in liver failure Hydromorphone Low Liver (glucuronidation) generation of toxic metabolites 1. Increased ½ life & variable onset 2. If used, reduce dose & frequency 1. Better choice if renal insufficiency. 2. Reduce dose & frequency in liver failure/cirrhosis Fentanyl High Liver CYP3A4 bioavailable w/liver failure Tramadol Low/mod Liver CYP 2D6/3A4 1. Safest long-acting drug in renal and liver failure. 2. Start lower dose patch in liver failure 1. Variable time to onset & analgesic efficacy in liver failure 2. Interactions w/other serotonergic medications MFMER slide-23

24 A Revised Pain Ladder for Patients with Renal Disease & Liver Failure/Cirrhosis Hydromorphone Gabapentin/Pregabalin Oxycodone (IR/CR forms) Fentanyl TD Referral to Specialist for Interventions Methadone Acetaminophen Topicals Functional assessment & referral to appropriate services at each step MFMER slide-24

25 Take Home Points In patients with severe renal impairment/dialysis, hydromorphone appears to be the safest short acting opioid. Opioids in liver failure can be used but need to start at lower doses and longer intervals Fentanyl patches can provide safer long-acting analgesia Morphine, codeine, tramadol all to be avoided 2013 MFMER slide-25

26 Case 3 BS is a 82-year-old female with moderate Alzheimer s dementia admitted to your hospital after a ground-level fall at her skilled care facility. She has a history of essential hypertension (well-controlled on amlodipine) & stage IV chronic kidney disease (basedline creatinine 2.1g/dL). Initial evaluation reveals displaced, left femoral neck fracture and she proceeds with surgical fixation. You are consulted by the surgical team to assist with medical management MFMER slide-26

27 Case 3 The patient has been receiving hydromorphone 2mg PO q6 hours on a standing basis & acetaminophen 1000mg PO q8hrs. Her other medications including amlodipine and donepezil are continued, and PRN orders are also placed: senna for constipation, albuterol nebulization solution for wheezing, zolpidem for sleep. Pain appears to be initially well-controlled, but on postoperative day 2, you are called to evaluate the patient for altered mentation. You find her agitated and actively hallucinating. Vital signs: Blood pressure 135 mmhg / 82 mmhg, and respiratory rate 16/min at rest with pulse oximetry at 94% on room air MFMER slide-27

28 While evaluating causes of her delirium, which of the following in the most correct next step in the management of her pain? A. Discontinue hydromorphone & replace with ibuprofen 400 mg every 6 hours for the next 48 hours. B. Discontinue hydromorphone & replace with tramadol 50 mg orally every 6 hours for pain. C. Decrease hydromorphone & start lidocaine patch x2 over left hip. D. Continue hydromorphone E. Discontinue hydromorphone & give lorazepam 0.25 mg IV once for agitation MFMER slide-28

29 Answer D. Continue hydromorphone 2013 MFMER slide-29

30 Opioids in the Elderly Patient Increased prevalence of renal and hepatic dysfunction. Increased sensitivity to opioid therapy Greater concern for drug-drug interactions Balance-Falls-Oh My! Watch those anticholinergic effects 2013 MFMER slide-30

31 A Revised Pain Ladder for Elderly Patients with Pain & a Serious Illness? Extended-release opioids Fentanyl TD Acetaminophen Topicals Referral to Specialist for Interventions Low dose hydromorphone or oxycodone Duloxetine Pregabalin Functional assessment & referral to appropriate services at each step MFMER slide-31

32 Take Home Points Opioids may be a cause of altered mental status in elderly patients with pain, but other causes of delirium should be considered, particularly in patients who appear to have previously tolerated opioids MFMER slide-32

33 Case 4 SM is a 59yoF with a long history of Type I diabetes mellitus complicated by end-stage renal failure, now receiving hemodialysis. She was admitted to your service for management of her severe bilateral lower extremity pain secondary to known calciphylaxis. Despite aggressive interventions her lesions continue to progress leading to ongoing severe pain managed with oral oxycodone sustained release and immediate release formulations with additional IV fentanyl pushes for severe pain. After many discussions with her Nephrology and Dermatology teams, she decides to forgo further disease directed therapies and focus on her comfort, which includes discontinuation of her dialysis MFMER slide-33

34 Case 4 Her analgesic regimen is changed over to a morphine continuous infusion of 1mg/hr with additional 2mg IV boluses available by PCA. Overnight she develops worsening pain and her infusion is increased several times. She is also given several doses of IV lorazepam which seem to help transiently overnight. In the morning, she is agitated, confused and yelling out intermittently in pain. When asked about her pain, she is unable to respond but appears to have diffuse pain to even light touch. HR 124. RR 20. Blood pressure is 88/54. Morphine infusion is currently at 5mg/hr. Extremities reveal deep ulcerations of her lower extremities bilaterally with intermittent myoclonus MFMER slide-34

35 What is the best option in the management of this patient? A. Haloperidol 2mg IV q4hrs needed for agitation B. Increase morphine to 6mg/hr but add in 6mg IV q10min by nursing administered bolus as needed C. Discontinue the morphine and start lorazepam 2mg IV q4hrs D. Discontinue morphine and start a lower dose fentanyl infusion with nursing administered boluses as needed 2013 MFMER slide-35

36 Answer D. Discontinue morphine and start a lower dose fentanyl infusion with nursing administered boluses as needed 2013 MFMER slide-36

37 Morphine Delirium Agitation Myoclonus Seizures Morphine-3-Glucuronide Morphine-6-Glucuronide Morphine-3-Glucuronide 2013 MFMER slide-37

38 When Signaling Goes Wrong Despite Our Attempts to fix it Hyperalgesia Increased pain response from normally painful stimulus. Sensitization Increased pain response from normal (typically nonpainful) stimulus. + Beginnings of new neurons that will fire with smaller and smaller stimuli. Peripheral & Central phenomenon 2013 MFMER slide-38

39 Opioid Associated Neurotoxicity MANIFESTATIONS Increasing sedation Agitation & delirium Hallucinations Myoclonus Seizures TREATMENTS Opioid rotation Dose reduction Hydration, magnesium replacement Avoid Confounders Adjuvants 2013 MFMER slide-39

40 Take Home Points Hyperalgesia mechanisms complex but involve both NMDA & glutamate-mediated pathways as well as potential direct toxic effects of active opioid metabolites. Treatment is opioid rotation, adjuvant NMDA blockade & supportive care MFMER slide-40

41 Using Opioids In Serious Illness Partridge et al., J Clin Oncol Oct 10;32(29): by American Society of Clinical Oncology 2013 MFMER slide-41

42 Questions & To cure sometimes, relieve often, comfort always. Dr. Edward Trudeau 2013 MFMER slide-42