Pharmacologic Considerations for Managing Sickle Cell Pain Claire Saadeh, PharmD, BCOP May 5, 2015

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1 Pharmacologic Considerations for Managing Sickle Cell Pain Claire Saadeh, PharmD, BCOP May 5, 2015 Table 1: Physiologic changes that occur during sickle cell pain crisis 1-3 Phase Description / Complications Prodromal phase (I) Occurs for approximately 1-2 days Symptoms: numbness, paresthesia, or aches in areas that later become painful Initial phase (II) Increase in pain Decreased RBC deformability Increased: # of dense cells, RCDW, Hb distribution width, reticulocyte count, and WBC Thrombocytopenia Established phase (III) Maximum pain severity Acute phase reactants & inflammatory response Gradual reversal of abnormalities from initial phase Resolving phase (IV) Pain decreases Rebound thrombocytosis, elevated fibrinogen levels, decreased RBC deformability, increased plasma viscosity è possible hypercoagulable state è crisis recurrence RBC = red blood cell; RCDW = red cell distribution width; Hb = hemoglobin; WBC = white blood cell Table 2: Suggested IV PCA Starting Doses for Opioid Naïve Adults 4,6-8 Morphine [1 mg/ml] Hydromorphone [0.2 mg/ml] Fentanyl [10 mcg/ml] Continuous IV (CIV) mg/hr mg/hr 0 5 mcg/hr infusion (caution) Demand dose* mg [1 mg] mg [0.2 mg] 5 25 mcg [10 mcg] Lockout interval 5-10 minutes 5 10 minutes 5 8 minutes Clinician bolus 2 mg Q 15 min 0.3 mg Q 15 min 10 mcg Q 10 min Maximum Doses (standard concentration) CIV: 6 mg/hr Demand: 3 mg Clinician bolus: 3 mg CIV: 6 mg/hr Demand: 3 mg Clinician bolus: 3 mg CIV: 200 mcg/hr Demand: 30 mcg Clinician bolus: 30 mcg *Onset of action 2-4 minutes 2 3 minutes 1 2 minutes *Time to peak effect minutes minutes 5 minutes *Duration of effect 2 hours 2 hours 1 2 hours [ ] indicates standard concentrations and standard doses at Sparrow Health System (SHS) Important notes: Basal rates in opioid naïve patients should be used with caution monitor closely for excess sedation +/- respiratory compromise/depression. It is suggested to initiate PCA without a basal (continuous) rate for opioid naïve patients & add on at a later time if no analgesic benefit from PCA demand dosing. Elderly patients (age > 65 years) consider lower doses (decrease by %) and/or increased lockout interval (10 minutes)

2 Table 3: Definitions Opioid Naïve Opioid tolerant NCCN 7 FDA 8 Patients who are not chronically Patients who do not meet the definition of opioid receiving opioid analgesics on a daily tolerant, and who have not taken opioid doses at basis least as much as those listed for opioid tolerant for Patients who are chronically receiving opioid analgesics on a daily basis NCCN: National Comprehensive Cancer Network; FDA: Food & Drug Administration Table 4: Converting an Opioid-Tolerant Patient to PCA 4,6 one week or longer Patients who are taking, > one week, at least: 60 mg PO morphine/day 25 mcg transdermal fentanyl/hour 30 mg PO oxycodone/day 8 mg PO hydromorphone/day 25 mg PO oxymorphone/day An equianalgesic dose of any other opioid Step 1 Consult patient s medication record for current opioid regimen Current policy at SHS is to discontinue all opioid analgesics while on PCA, unless specified Patients receiving methadone or transdermal fentanyl patches contact prescriber Step 2 Determine which opioid to switch to IV PCA Morphine (preferred) or hydromorphone (or fentanyl) Step 3 Current Oral Opioid Regimen (if applicable) Determine the 24 hour utilization of each PO opioid (ATC & PRN s) Use opioid equianalgesic tables to convert each PO opioid to PO morphine equivalents per day Convert total PO morphine dose per day to IV morphine equivalents per day Step 4 Current Transdermal Fentanyl Patch (if applicable) Determine how long patient has been receiving transdermal fentanyl patch Contact prescriber to continue or discontinue patch If discontinuing patch and patient is opioid tolerant, use opioid equianalgesic tables to convert transdermal patch to PO morphine equivalents per day, then convert to IV morphine equivalents per day Step 5 Current IV Opioid Regimen (if applicable) Determine the 24 hour utilization of each IV opioid (ATC & PRN s) Use opioid equianalgesic tables to convert each IV opioid to IV morphine equivalents per day Step 6 Total IV morphine equivalents per day Add total IV morphine equivalents per day from step 3 (if applicable), step 4 (if applicable), and step 5 (if applicable) Step 7 If using hydromorphone or fentanyl for IV PCA Use opioid equianalgesic tables to convert IV morphine equivalents per day to IV hydromorphone or fentanyl equivalents per day Step 8 Determine PCA continuous infusion rate per hour Divide total IV morphine (or hydromorphone or fentanyl) equivalents per day by 24 to determine rate in mg per hour (or mcg per hour for fentanyl) Step 9 Step 10 Calculate PCA demand dose PCA demand dose = 50% of hourly rate Interval = Q 30 minutes (may consider Q 15 minutes for fentanyl) Assess & re-assess! 2

3 Table 5: Follow Up / Next Steps / Continued Assessment 4,6 Clinical Situation / Assessment relief No adverse effects relief Adverse effects Adverse effects Excess sedation immediately after PCA demand dose relief during activity Somnolent patient, difficult to arouse, or respiratory depression Disproportionate number of injections & attempts Proposed Intervention Administer clinician bolus Increase opioid dose by 25 50% (PCA demand and/or CIV basal rate) Consider adding a basal rate if patient only receiving PCA demand (use caution) Consider adjuvant agents if not already utilized Decrease opioid dose by 25 % (PCA demand and/or CIV basal rate) Consider rotation to a different opioid If opioid-naïve & receiving basal PCA, discontinue basal rate Decrease opioid dose by % (PCA demand and/or CIV basal rate) Consider rotation to different opioid Decrease PCA demand dose by % and shorten the lockout interval Consider rotation to different opioid Remind patient to use PCA demand dose 2 5 minutes prior to activity Continue to use demand dose during activity (as lockout interval allows) Review patient chart & medication list rule out other causes If opioid-naïve, discontinue opioid (especially continuous infusion) If opioid tolerant, reduce opioid dose by 75 % - discontinuation of opioid may precipitate opioid withdrawal Consider naloxone Add non-opioid adjuvant If opioid therapy needs to continue, re-start opioid dose at 50 % of previous dose If ratio is 1 injection for less than 2 or 3 attempts and patient has no pain, no interventions required If ratio is 1 injection to less than 2 or 3 attempts, patient has pain, adverse effects are tolerable/managed, consider increasing opioid dose by % If ratio is 1 injection to > 3 attempts, patient has pain, adverse effects are tolerable/managed, consider clinician bolus. Educate patient about waiting for lockout interval before pushing button again Table 6: Approximate Equianalgesic Opioid Conversions 6 Opioid Agonist Approximate Equianalgesic Dose Oral Parenteral Morphine 30 mg 10 mg Hydromorphone 7.5 mg 1.5 mg Oxycodone mg 10 mg Oxymorphone 10 mg 1 mg Hydrocodone 30 mg N/A Fentanyl Transdermal patch 25 mcg/hr = Morphine 60 mg PO / day Fentanyl IV 25 mcg/hr = Morphine IV 1 mg/hr Methadone Consult the appropriate resources! 3

4 Table 7: Rules for Opioid Rescue Dosing (not for patients receiving PCA)* PO** IV** 1. Calculate the total opioid mg per 24 hour period (convert to ONE opioid) 2. Give % every 1-2 hours as needed 1. Calculate the total opioid mg per hour (i.e. rate per hour) 2. Give % of hourly dose every minutes as needed *For patients with chronic pain and receiving a sustained release opioid product around the clock or an IV opioid infusion **It is preferred to utilize the same opioid for rescue as that used for maintenance (or around the clock) therapy. Exceptions may include methadone or fentanyl transdermal patches [use morphine immediate release (or other equivalent opioid) administered as an oral solution or tablet] Appendix Basic PCA Pump Features 4 Drug concentration: concentration of drug per milliliter solution in drug reservoir Drug reservoir volume: amount of solution in drug reservoir PCA bolus dose: amount patient will receive each time a bolus is self-administered Lockout (delay) interval: amount of time that must elapse between PCA doses administered Basal rate: amount of the continuous infusion (optional) Hour limit: the maximum amount the patient can receive in 1 hour or 4 hours by PCA bolus doses and basal rate (may be optional feature on some pumps) Important history available in most PCA pumps: o PCA attempts: number of times the patient presses the PCA button o PCA injections: number of times the patient successfully self-administers a PCA dose o Volume given o Volume remaining in drug reservoir 4

5 References 1. McCaffery M, Pasero C. Pain Clinical Manual. 2 nd ed. St. Louis: Mosby, Inc; c1999. Chapter 12, Selected pain problems, sickle cell disease-related pain; p American Pain Society. Guideline for the Management of Acute and Chronic Pain in Sickle Cell Disease Ballas SK, Gupta K, Adams-Graves P. Sickle cell pain: a critical reappraisal. Blood. 2012;120(18): Pasero C, McCaffery M. Pain assessment and pharmacologic management. 1st ed. St. Louis: Mosby, Inc.; c2011. Chapter 12, key concepts in analgesic therapy; p and chapter 17, intravenous patientcontrolled analgesia; p DeBaun MR, Vichinsky EP. Acute pain management in adults with sickle cell disease. UpToDate. Accessed March 31, McPherson ML. Demystifying opioid conversion calculations. A guide for effective dosing. Bethesda: American Society of Health System Pharmacists;2010. Chapter 7, Patient-controlled analgesia and neuraxial opioid therapy; p National Comprehensive Cancer Network (NCCN). Clinical practice guidelines in oncology: adult cancer pain v Available at: Accessed March 31, U.S. Food and Drug Administration. Extended-release (ER) and long-acting (LA) opioid analgesics risk evaluation and mitigation strategy (REMS). Silver Springs, MD: Available at: ucm pdf. Accessed March 31, Wright J, Ahmedzai. The management of painful crisis in sickle cell disease. Curr Opin Support Palliat Care. 2010;4: Gonzalez ER, Bahal N, Hansen LA, et.al. Intermittent injection vs patient-controlled analgesia for sickle cell crisis pain. Arch Intern Med. 1991;151(7): Melzer-Lange MD, Walsh-Kelly CM, Lea G, et.al. Patient-controlled analgesia for sickle cell pain crisis in a pediatric emergency department. Pediatric Emergency Care. 2004;20(1): van Beers EJ, van Tuijn CFJ, Nieuwkerk PT, et.al. Patient-controlled analgesia versus continuous infusion of morphine during vaso-occlusive crisis in sickle cell disease, a randomized controlled trial. Am J Hematol. 2007;82: Field JJ, Knight-Perry JE, DeBaun MR. Acute pain I children and adults with sickle cell disease: management in the absence of evidence-based guidelines. Curr Opin Hematol. 2009;16: Guidance: Evidence-Based Management of Sickle Cell Disease Expert Panel Report Available at: Accessed February 8, Yawn BP, Buchanan GR, Afenyi-Annan AN, et. al. Management of sickle cell disease. Summary of the 2014 evidence-based report by expert panel members. JAMA. 2014;312(10): Excerpts/content of this presentation have also been taken from the following online publication: Saadeh C. Clinical Guide to the Pharmacologic Treatment Options for Pain. Available at: 5