Opioid Use in Serious Illness

Opioid Use in Serious Illness Jeanie Youngwerth, MD University of Colorado School of Medicine Associate Professor of Medicine, Hospitalist Director, Palliative Care Service Associate Director, Colorado Palliative Medicine Fellowship Program Medical Director, Halcyon Hospice and Palliative Care Pain: Objectives Apply equianalgesic opioid conversions in acute pain management Discuss principles for opioid dosing and titration for acute pain Describe adjustments for opioids in the setting of renal or liver failure 47 y/o M with metastatic neuroendocrine tumor Oxycodone ER 80 mg po BID Hydromorphone IR 4 mg po q 4 hrs prn pain 6 tablets a day Acute pain crisis from tumor burden Cr 0.7;;LFTs WNL Put on PCA overnight by moonlighter

What are the most appropriate PCA settings? 1. Morphine IV basal 1 mg/hr;; demand 2 mg;; lockout 8 min 2. Hydromorphone IV basal 1 mg/hr;; demand 1 mg;; lockout 10 min 3. Oxycodone ER 80 mg po BID plus Hydromorphone IV no basal;; demand 0.2 mg;; lockout 6 min 4. Morphine IV basal 3 mg/hr;; demand 1.5 mg;; lockout 10 min PCA Errors #1 improper dose/quantity US Pharmacopeia 2004;; Hicks: Am J Health Syst Pharm 2008. Opioid Conversions Equianalgesic Dosing 1. Calculate total 24 hour total opioid dose 2. Convert to 24 hour new opioid equivalent 3. Adjust by 50-75% for incomplete cross tolerance 4. Triple check calculations 5. Constipation prophylaxis! EPEC Module 4 1999;; www.core-rems.org 2013 v1.0;; NCCN: Adult Cancer Pain v1.2016.

Incomplete Cross Tolerance When switching from one opioid to another Tolerance developed to one opioid may not completely transfer to the new opioid Start the new opioid at 50-75% of the equianalgesic dose 60% good generalization Pasternak: Trends in Pharm Sciences 2001;; Ballantyne: NEJM 2003;; Mehta: Anaesth 2006;; www.core-rems.org 2013 v1.0;; NCCN: Adult Cancer Pain v1.2016. Opioid Conversions Equianalgesic Dosing Current Opioid Total 24 hour Current Opioid = New Opioid Total 24 hour New Opioid (X) Choice of Opioid What is considered the gold standard opioid? Grass: Anesth Analg 2005.

1. Calculate total 24 hour opioid dose Oxycodone ER 160 mg / day + Hydromorphone IR 24 mg / day TDD = Morphine X mg IV / day 2. Convert to 24 hour new opioid equivalent Current Opioid New Opioid = Total 24 hour Current Total 24 hour New (X) Oxycodone 20 mg po Morphine 10 mg IV = Oxycodone 160 mg/day po Morphine IV X X = Morphine 80 mg IV/day 2. Convert to 24 hour new opioid equivalent Current Opioid New Opioid = Total 24 hour Current Total 24 hour New (X) Hydrom 7.5 mg po Morphine 10 mg IV = Hydrom 24 mg/day po Morphine IV X X = Morphine 32 mg IV/day

3. Adjust by 60% for incomplete x- tolerance Morphine 80 + 32 = 112 mg IV / day X 0.6 = Morphine 67 mg IV / day * Pain Pearl * Adjust for incomplete cross tolerance 4. Triple check calculations 5. Constipation prophylaxis! -Senna 2 tabs po BID Hawley: JPSM 2008;; Librach: JPSM 2010;; Tarumi: JPSM 2013.

Morphine 67 mg IV / day PCA settings? Morphine 67 mg IV / day 24 hrs = 2.8 mg/hr Basal 3 mg/hr Demand dose Lockout time Nurse-bolus PCA Management FIRST ask yourself Opioid naïve or not??? PCA Parameters Basal Demand Lockout

PCA Basal Rate- Opioid Tolerant Convert 24 hour total opioid requirement to hourly rate (by equianalgesic dosing) Macintrye: Br J Anaesth 2001;; Lehmann: JPSM 2005;; Grass: Anesth Analg 2005. PCA Basal Rate- Opioid Naïve No basal rate Increased rates of respiratory depression No improvement in pain scores Sidebotham: JPSM 1997;; Macintrye: Br J Anaesth 2001;; Krenn: Euro J Pain 2001;; Didem: Can J Anesth 2003;; Grass: Anesth Analg 2005;; Herr: Iowa City Guideline Summary NGC-5382 2006.

PCA Demand Dose- Opioid Tolerant 50% of the basal rate (50-100%) Grass: Anesth Analg 2005. PCA Demand Dose- Opioid Naive Morphine Outcome demand dose 0.5 mg Inadequate analgesia Opioid Naive 2 mg é Respiratory depression 1 mg Optimum balance Owen: Anaesth 1989;; Sidebotham: JPSM 1997.

PCA Lockout Time Based on time to peak effect IV: 8-10 min Plasma Concentration Cmax SC / IM: 20-30 min PO / PR: 60-90 min Time Half-life (t 1/2 ) PCA Lockout Time Morphine 7 vs 11 minutes Fentanyl 5 vs 8 minutes No difference in pain, anxiety or side effects Ginsberg: Pain 1995.

PCA Lockout Time 10 minutes is a standard interval Ginsberg: Pain 1995;; Macintrye: Br J Anaesth 2001;; Walder: Acta Anaesthesiol Scand 2001;; Grass: Anesth Analg 2005. PCA Nurse Initiated Bolus Not studied Up to twice the demand dose Grass: Anesth Analg 2005. Morphine 67 mg IV / day 24 hrs = 2.8 mg/hr Basal 3 mg/hr Demand dose 1.5 mg Lockout time 10 min Nurse-bolus 3 mg

PCA Dosing Summary Basal Rate Opioid naïve: none Opioid tolerant: Convert 24 hour total opioid requirement to hourly rate (by equianalgesic dosing) Demand Dose Opioid naïve: 1 mg IV Morphine equivalent Opioid tolerant: 50% (100%) of the basal rate Lockout Time 10 minutes Nurse Initiated Bolus Up to 2x the demand dose Nurse calls 3 hours later for patient with severe pain. What is the best next step when titrating the PCA for acute pain control? 1. Increase basal rate to 4 mg/hr 2. Increase demand dose to 3 mg 3. Decrease lockout time to 6 minutes 4. Opioid rotation to PCA IV Fentanyl 5. Add Oxycodone/Acetaminophen 5/325 one tablet oral q4 hours prn Opioid Titration Acute control: immediate release/prn Demand dose Chronic control: sustained release/scheduled Basal rate Hanks: British J Cancer 2001;; Grass: Anesth Analg 2005.

* Pain Pearl * Titrate the demand dose for acute pain PCA Demand Dose Titration Practically every 60 minutes and reevaluate Can change every 10-15 minutes if needed Opioid Titration Pain Severity Increase Dose By Mild 25% Moderate 50% Severe 100% EPEC Module 4 1999;; NCCN Adult Cancer Pain V.1.2016.

PCA Basal Rate Titration Every 24 hours reasonable 8-24 hours to achieve steady state Avoid changing more frequently than q 8 hrs EPEC Module 4 1999;; APS 2003. PCA Basal Rate Titration Dose based on 24 hour total opioid usage Patient pain rating Your assessment Daily trend of 24 hr requirements PCA Titration Summary Basal rate Consider change ~ daily based on 24 hour use Demand dose Titrate for acute pain control é 25% mild pain é 50% moderate pain é 100% severe pain Lockout time 10 min

PCA to Oral Opioids Once stable opioid requirements for ~2 days Use TDD from PCA to calculate equianalgesic oral dose of new opioid Patient using TDD Morphine 130 mg IV / day PCA to Oral Opioid Current Opioid New Opioid = Total 24 hour Current Total 24 hour New (X) Morphine 10 mg IV Morphine 30 mg po = Morphine 130 mg/day IV Morphine po X X = Morphine 390 mg po/day (no x-tolerance needed)

PCA to Oral Opioid X = Morphine 390 mg po/day Morphine ER 200 mg po BID BTP? Avoid Mixing Opioids é risk for confusion and mistakes by patients and providers SIMPLIFY Morphine SR + Morphine IR prn NCCN: Adult Cancer Pain v1.2016. * Pain Pearl * Breakthrough pain IR Dose: 10-15% of 24 hour total opioid dose Interval: time to peak effect NCCN: Adult Cancer Pain v1.2016.

PCA to Oral Opioid X = Morphine 390 mg po/day Morphine ER 200 mg po BID BTP: Morphine IR 45 mg (30 mg x 1.5 tab) po q1 hr prn pain Or Morphine elixir 20 mg/ml 40 mg po q1 hr prn pain Poop Prophylaxis: Senna 2 tab po BID When to Avoid Morphine Renal Failure Majority of opioids renally cleared Recommendations based on presence of active metabolites Limited studies;; no RCTs No consensus on GFR Dean: J Pain Symptom Manage 2004;; King: Palliat Med 2011.

Renal Failure (RF) Morphine, Codeine Potent, active metabolites cleared renally Increased risk for neurotoxicity Avoid in RF Hydromorphone, Oxycodone, Tramadol Poorly studied Cautious dosing Fentanyl Limited studies No known active renal metabolites No dose adjustment short term in RF consider decreasing dose long term Dean: J Pain Symptom Manage 2004;; King: Palliat Med 2011. Liver Failure Impaired oxidation and glucuronidation Limited studies- most extrapolated from RF High prevalence & risk of RF in cirrhosis Avoid Morphine, Codeine, Tramadol Transdermal preparations Davis: Clin Pharmacokinet 2007;; Rhee: J Palliat Med 2007;; Chandok: Mayo Clin Proc 2010. * Pain Pearl * Avoid Morphine in renal/liver failure Fentanyl safer choice in RF Oxycodone and Hydromorphone cautious dosing Consider IR preparations Consider longer dosing intervals

Caveats Methadone Elderly Fentanyl TD Methadone Does not follow regular opioid principles! Recommend consulting Palliative Care or Pain Service for patients in acute pain crisis who are on Methadone Bruera: JPM 2002. Elderly- Opioid Reduction Require less opioid than younger patients to achieve same relief Opioid sensitivity é by 50% Pain intensity ê by 10-20% each decade after age 60 Herr: Iowa City Guideline Summary NGC-5382 2006.

Elderly- Opioid Reduction Initiate opioids at 25-50% lower dose than recommended for younger adults Herr: Iowa City Guideline Summary NGC-5382 2006. Evidence Grade = B;; www.core-rems.org 2013 v1.0. Fentanyl TD Chronic, stable pain in opioid-tolerant Lipophilic;; ê absorption in cachectic é absorption with heat (fevers) NCCN: Adult Cancer Pain v1.2016;; Reddy: JPSM 2016. Fentanyl TD 2x po Morphine Fentanyl TD 200 mg po QD 100 mcg/hr TD q3 days Fentanyl TD 2.4x po Morphine 100 mcg/hr TD q3 days 240 mg po QD NCCN: Adult Cancer Pain v1.2016;; Reddy: JPSM 2016.

Improve Pain: QI Projects PCA Safety Checklist Safe, effective, rapid pain control with a standardized, transparent approach PCA Safety Checklist FOR ALL STEPS: Document exceptions to any step of the safety checklist. Address psycho- social- spiritual pain. INITIATION Patient has confirmed cognitive function physical capability Patient and family educated - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - Document PCA indication Discontinue all other opioids - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - CALCULATIONS GUIDELINES 40% reduction for cross tolerance when converting to another opioid For basal and demand: Is demand 50-100% of basal rate? Is RN bolus 100-200% of demand? Is demand lockout 10 minutes? Double check calculations with a palliative care team member - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - PCA conversion verbally communicated to primary team and nurse Is patient IPC bed status? Document conversion calculations (.pccalc and.pcpca) TITRATION CALCULATIONS GUIDELINES Incremental 24 hour basal rate increase not to exceed 100% of previous basal rate For basal and demand: Is demand 50-100% of basal rate? Is RN bolus 100-200% of demand? Is demand lockout 10 minutes? Double check previous 24 hour use with a palliative care team member Double check titration calculations with a palliative care team member - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - PCA titration verbally communicated to primary team and nurse - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - Document titration calculations (.pcpca) TRANSITIONING Patient has confirmed GI absorption renal function appropriate for medication - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - CALCULATIONS GUIDELINES Stable PCA use x 48 hours 40% reduction for cross tolerance when converting to another opioid Is oral PRN dose 10-15% of total daily dose? Double check calculations with a palliative care team member - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - Patient has confirmed outpatient insurance coverage outpatient provider follow up - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - PO conversion verbally communicated to primary team and nurse - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - Document conversion calculations (.pccalc) PCA Safety Checklist current 24 hour dose *** = New X current ratio*** new ratio*** Total X = *** mg Total X 60% incomplete cross tolerance = *** mg Based on this Date calculation, Basal patient's Demand report Lockout of pain, Total and Usemy assessment Avg per hour of patient, Recommend: **** PCA table Opioid: *** Date Basal Demand Lockout Total Use Avg per hour

Percent Decrease from Moderate- Severe Pain to No- Mild Pain Within 2 Days Cycle 1 = 85% Pre = 42% 14/18 Cycle 2 = 54% 11/17 13/21 7/14 9/18 Patients with ESAS pain scores assessed at day 1 and day 3 (or day 2, if day 3 data not available);; Data Collection Utilizing EPIC Reports Resources REMS https://search.er-laopioidrems.com/guest/guestpageexternal.aspx NCCN Adult Cancer Pain Guidelines http://www.nccn.org/professionals/physician_gls /f_guidelines.asp * Pain Pearls * Adjust for incomplete cross tolerance (60%) Titrate demand dose for acute pain 25% mild pain 50% moderate pain 100% severe pain BTP: 10-15% of TDD Avoid Morphine with renal / liver failure