Pain Management in Sickle Cell Anemia

7/10/2019

#FSHP2019 Disclosure #FSHP2019

I do not have (nor does any immediate family member Pain Management in have): – a vested interest in or affiliation with any corporate Sickle Cell Anemia organization offering financial support or grant monies for this continuing education activity – any affiliation with an organization whose philosophy could potentially bias my presentation Joseph Cammilleri, Pharm.D, BCACP, CPE Ambulatory Care Clinical Pharmacist UF Health Jacksonville

Objectives #FSHP2019 #FSHP2019

• Describe the types and characteristics of pain associated with sickle-cell disease • Discuss treatment of pain in patients with sickle-cell disease • Review clinical pearls in the management of acute versus chronic pain

Saunthararajah, Y., et al. Sickle Cell Disease: Clinical Features and Management. Hoffman: Hematology 2012. 34

Pathophysiology #FSHP2019 Pathophysiology #FSHP2019

Hb A Hb S Ischemia/Reperfusion Vascular Occlusion

Solubility Soluble Insoluble O2 Systemic Inflammation

O2 Exposed hydrophobic Deoxygenation Maintains Shape Endothelial pockets Dysfunction

Healthy ‘Sticky,’ rigid RBC Effects Lifespan ~120 days Lifespan 10-20 days Hemolysis Anemia, heme release

CDC. Sickle Cell Disease. August 2017. Nat Rev Nephrol. 2015 Mar; 11(3): 161–171. Pharmacotherapy: A Pathophys Approach. 9th ed; 2014. Image: practicalpainmanagement.com/resources 56

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Genetics #FSHP2019 Prevalence #FSHP2019 • Sickle Cell Disease • 1:396 AA Births • 1:36,000 H Births

• Sickle Cell Anemia • Hb SS • Hb S-β thal • Hb SC

AA= African American

H= Hispanic Saunthararajah, Y., et al. Sickle Cell Disease: Clinical Features and Management. Hoffman: Hematology 2012. F Piel et al Sickle Cell Disease N Engl J Med 2017; 376:1561-1573 78

Diagnosis #FSHP2019 Complications #FSHP2019

• CBC Acute Chronic • Peripheral smear VOCs Retinopathy

Infection (IPD) Nephropathy Pulmonary Disease • Solubility test Priapism Osteonecrosis Acute Chest Syndrome Delayed growth • Hb electrophoresis Stroke Stasis Ulcers Splenic Sequestration Increased risk of Infection

VOC = vaso-occlusive crisis; Peds in Review. 2012; 33 (5): 195. Lancet. 2017; 390:311-23. Saunthararajah, Y., et al. Sickle Cell Disease: Clinical Features and Management. Hoffman: Hematology 2012. IPD = Invasive pneumococcal disease Pharmacotherapy: A Pathophys Approach. 9th ed; 2014. 910

Infection #FSHP2019 Fever #FSHP2019

• Abnormal immune function • Medical emergency

• Immunizations • IV antibiotics • Temp >101.3 • Penicillin prophylaxis • Penicillin VK 125mg once daily (3yo) • Penicillin VK 250mg BID

Peds in Review. 2012; 33 (5): 195. Peds in Review. 2012; 33 (5): 195. Lancet. 2017; 390:311-23. Lancet. 2017; 390:311-23. Pharmacotherapy: A Pathophys Approach. 9th ed; 2014. Pharmacotherapy: A Pathophys Approach. 9th ed; 2014. 11 12

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Dactylitis #FSHP2019 Splenic Sequestration #FSHP2019

• Hand-foot syndrome • Life-threatening • Treatment • Fluids/blood transfusion • Splenectomy • Inflammation • Primarily in infants

• Pain medication • Symptoms • Engorgement of the spleen • Hypovolemia • Decrease hemoglobin

Acute Chest Syndrome #FSHP2019 Priapism #FSHP2019

• 2nd most common reason • Treatment • Painful Erection for admission • Blood transfusion/fluids • Oxygen • Antibiotics • Common • Sign/Symptoms • 90% by 20yo • New radiodensity • Fever • Treatment • Respiratory distress • Supported therapy (sitz bath/pain medication) • Pain • Aspiration of blood

Kidney Disease #FSHP2019 Neurologic Complications #FSHP2019

• Gross hematuria • Strokes (11%-20%) • Papillary necrosis • Treatment - Oxygen and blood transfusion • Primary Prevention – Blood transfusion • Nephrotic syndrome • Secondary Prevention – Blood transfusion • Renal infarction Up to 18% CKD • Hyposthenuria • Headache • Pyelonephritis • Renal medullary carcinoma • Seizures

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Iron Overload #FSHP2019 Hydroxyurea #FSHP2019

• Cause – Blood transfusions • Class: ribonucleotide reductase inhibitor • Mechanism: stimulates production of • Consequences – Organ damage Hemoglobin F (HbF) • Stimulate erythropoiesis • NO release and synthesis • Assessment - MRI, Biopsy, Ferritin level • Antioxidant effects • Uses: • Treatment – Chelating agents • Prolong duration between SCD relapses • Delay organ damage

HbF = fetal hemoglobin Peds in Review. 2012; 33 (5): 195. Peds in Review. 2012; 33 (5): 195. Lancet. 2017; 390:311-23. SCD = sickle cell disease NHLBI. SCD Guidelines. 2014. Pharmacotherapy: A Pathophys Approach. 9th ed; 2014. NO = nitric oxide Pharmacotherapy: A Pathophys Approach. 9th ed; 2014. 19 20

#FSHP2019 #FSHP2019 Multicenter Study of Hydroxyurea Multicenter Study of Hydroxyurea Charache, et al. (1995) Charache, et al. (1995)

Objective Occurrence of Acute Pain Crises

• Determine efficacy of hydroxyurea in reducing frequency of SCD crises • 44% reduction of acute crises per year (2.5 vs 4.5 crises; p<0.001) • 58% reduction in crises requiring hospitalization (1 vs 2.4 crises; p<0.001) Design

• Randomized (1:1), double-blind, placebo-controlled Other Outcomes • Planned 24-month follow-up • Prolonged time to first crisis (3 vs 1.5 months; p=0.01) Inclusion (n=299) • Decreased incidence of acute chest syndrome (25 vs 51 patients; • Adults >18 years with ≥ 3 crises in the year prior to enrollment p<0.001) • Excluded HbSβ0, HbSβ+ • Interruption for myelosuppression was more common with hydroxyurea (14 vs 6 patients)

SCD = Sickle cell disease 0 + NEJM. 1995. 20 (322):1317-22. HbSβ / HbSβ = β -thalassemia major/minor NEJM. 1995. 20 (322):1317-22. 21 22

Hydroxyurea in Pediatrics #FSHP2019 Hydroxyurea: Indications #FSHP2019

Acute or recurrent VOC complications Ferster, et al. (1996) Wang, et al. (2011; BABY HUG)

• Single-blind, cross-over in • Randomized trial in children <18 children (N=25) with ≥ 3 months (N=193) crises per year Evidence of Organ Dysfunction • Primary Outcome: incidence of • Primary Outcomes splenic sequestration • Decreased hospitalization (6 • Thornburg et al (2012) vs 19 patients; p=0.0016) • 52% reduction in pain crises • Decreased hospital stay (5.3 15 mg/kg/day starting dose, titrated to mild toxicity (p<0.001) vs 15.2 days; p=0.0027) • 81% reduction in dactylitis • Did not report ADEs (p<0.001) • 28% reduction in hospitalization Limitations: Dose-related toxicity | Adherence requirements | Inadequate response

Blood. 1996; 88 (6): 1960-4. NHLBI. SCD Guidelines. 2014. Lancet. 2011;377(9778):1663-72. Hematology. 2009; 62-9. Blood. 2012; 120(22):4304-10. VOC = vaso-occlusive crisis Ann Int Med. 2008; 148 (12): 939-55. 23 24

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Pain #FSHP2019 Acute Pain #FSHP2019 • IV Opioids • Cardinal feature • Precipitating factors: • Scheduled doses provide superior control • Vaso-occlusive crisis • Physical stress Udezue, et al. (2007) - RTC analgesics vs demand doses increased discharge at • Infection 72 hours (83% vs 71%; p<0.05) • Dehydration • Hypoxia • PCA • Acidosis • Benefits over scheduled infusion • Cold Van Beers, et al. (2007) - Decreased cumulative morphine consumption vs standard care at 3 days (p=0.018) • Swimming for •Non-significant reduction in pain scores (4.9 vs 5.3; p=0.09) prolonged periods

PCA – Patient controlled analgesia RTC = round the clock NHLBI. SCD Guidelines. 2014. W Afr J Med. 2007; 26(3): 179-82 Saunthararajah, Y., et al. Sickle Cell Disease: Clinical Features and Management. Hoffman: Hematology 2012. RCT = randomized controlled trial Am J Hematol. 2007; 82:955-60. 25 26

Acute Pain #FSHP2019 Chronic Pain #FSHP2019 • Ketamine • MSH (1995) • NMDA antagonist • Pain medication required 40% of the time, up to 80% • Low dose infusion immediately following VOC

• PiSCES (2005) • Adults reported SCD- related pain 55% of the time Image: http://drsunderman.com/dehydration-joint-pain/ Pain MME

NHLBI. SCD Guidelines. 2014. NEJM. 1995. 20 (322):1317-22. J Pain Palliative Care Pharmacotherapy. 2018 Mar;32(1):20-2 Health Qual Life Outcomes. 2005; 3 (50). 27 28

Chronic Pain #FSHP2019 Methadone #FSHP2019

• Identifiable • Synthetic opioid • Vertebral fractures • µ agonist • Avascular necrosis • NMDA receptor antagonist • Osteoarthritis • Skin ulcers • Fast onset and long duration of action • Treatment • Opioids • Variable half-life • Adjunctive agents

Saunthararajah, Y., et al. Sickle Cell Disease: Clinical Features and Management. Hoffman: Hematology 2012. Dolophine (methadone) package insert. Columbus, OH: Roxane Laboratories, Inc; Accessed April 2019. 29 30

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Metabolism #FSHP2019 Methadone Dangers #FSHP2019

• Hepatic – CYP450 • Drug interactions • CYP3A4 • CYP2B6 • • CYP2C19 QTc prolongation

• Inactive metabolites • Inappropriate dosage/titration

Dolophine (methadone) package insert. Columbus, OH: Roxane Laboratories, Inc; Accessed April 2019. Dolophine (methadone) package insert. Columbus, OH: Roxane Laboratories, Inc; Accessed April 2019. 31 32

Drug Interaction #FSHP2019 Enzyme Inhibitors/Inducers#FSHP2019

• Pharmacokinetic Enzyme Inhibitors Enzyme Inducers • Enzyme inhibitors Fluconazole Rifampin Clarithromycin Phenytoin • Enzyme inducers Ketoconazole Phenobarbital Erythromycin Carbamazepine Diltiazem • Pharmacodynamic Verapamil • CNS depressants Grapefruit Juice • QT prolonging medications

Dolophine (methadone) package insert. Columbus, OH: Roxane Laboratories, Inc; Accessed April 2019. 33 34

Effect #FSHP2019 CNS Depressant #FSHP2019

• Many drug interactions Situation Result Risk Action • Anxiolytics • Opioids Methadone with a Increased serum Overdose Reduce dose • Muscle relaxants enzyme inhibitor methadone level ADRs • Results Methadone with a Decreased serum Uncontrolled pain Increase dose • Additive respiratory depression enzyme inducer methadone level Use break-through • Hypotension medications • Sedation • Coma

Dolophine (methadone) package insert. Columbus, OH: Roxane Laboratories, Inc; Accessed April 2019. 35 36

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Respiratory Depression #FSHP2019 QTc Prolongation #FSHP2019

• Symptoms • Potential for fatal arrhythmia • Reduced urge to breath • Decreased respiratory rate • Sighing breathing pattern • Risk factors • Older age • Female • Monitored Naloxone • Structural heart disease • Conversion • Electrolyte abnormalities • Initiation • Long QT syndrome • Dose increase

Justo D, et al. Addiction 2006;101:1333–8. Walker PW, et al. Pain 2003; 103: 321-4. 37 38

QTc Prolongation #FSHP2019 Methadone Dosage #FSHP2019

• Inform patients of arrhythmia risk • Opioid naive: 2.5mg Q8h

• Obtain complete cardiac history • Dose conversion • Convert to morphine equivalents • Obtain ECG to stratify risk • Not linear! Ratio • Pretreatment, in 30days, and annually • QTc 451-499ms risk vs. benefits • Refer to dosing chart • QTc ≥ 500ms avoid

Justo D, et al. Addiction 2006;101:1333–8. Walker PW, et al. Pain 2003; 103: 321-4. 39 40

Dosage Conversion #FSHP2019 Dosage Conversion #FSHP2019 Mercadante, 2001 • Methadone prescribing info: Morphine Dose 30-90 90-300 >300 • < 100mg MS (20-30% ME) (mg/day) Ratio 4:1 8:1 12:1 • 101-300mg MS (10-20% ME) Ayonrinde, 2000 • 300-600mg MS (8-12% ME) Morphine Dose 101- 301- 801- (mg/day) <100 601-800 ≥1000 • 600-1000mg MS (5-10% ME) 300 600 1000 • >1000mg MS (<5% ME) Ratio 3:1 5:1 10:1 12:1 15:1 20:1 • Modified Morley-Makin UK Model (Friedman) • < 1000mg/day morphine < 65yo = 10:1 MS= morphine sulfate • < 1000mg/day morphine > 65yo = 20:1

ME= methadone equivalents Dolophine (methadone) package insert. Columbus, OH: Roxane Laboratories, Inc; 2012 Jul. McPherson, Mary Lynn M. (2010). Demystifying opioid conversion calculations: a guide for effective dosing. American Society of Health-System Pharmacist. 41 42

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Methadone Candidates #FSHP2019 #FSHP2019

Appropriate Inappropriate

• True morphine allergy • Drug interactions • Renal impairment • Cardiac risk factors • Cost • Non-adherence • Long-acting medication • Poor cognitive function

43 44

Endari™ (L-glutamine) #FSHP2019 Summary: L-glutamine #FSHP2019

• FDA Approved July 2017 • L-glutamine decreased frequency of pain crises • Adults and children (≥5 years) through 48 weeks • Decreased frequency of acute chest syndrome • Class: essential amino acid • Benefits are consistent regardless of hydroxyurea • Mechanism: Undefined administration • Protective, antioxidant effects • Limitations • Thought to restore RBC redox potential • High overall dropout rate (32%) • Dose: 15g po BID • Population with ‘high’ baseline hemoglobin (8.8 g/dL) • Low yearly crisis rate • No quality of life outcomes

Endari [package insert]. 2018. Emmaus Medical, Inc. Torrance, CA. NEJM. 2018; 379(3):226‐235. RBC = Red blood cell NEJM. 2018; 379(3):226‐235. Endari [package insert]. 2018. Emmaus Medical, Inc. Torrance, CA. 45 46

Is SCD Curable? #FSHP2019 #FSHP2019

Produce virus with Isolate target cells Ex Vivo transduction of Re-infused modified 1.therapeutic payload 2. (HSCs or T cells) 3. target cells 4. host cells

Bluebirdbio. 2018. Online: www.bluebirdbio.com Exp Heme. 2018; 64:12‐32. HSCs = hematopoietic stem cells NEJM. 2018; 378 (16): 1479‐93. 47 48