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 12 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 1 7/10/2019 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 2 7/10/2019 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 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. 13 14 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 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. 15 16 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 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. 17 18 3 7/10/2019 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 4 7/10/2019 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 5 7/10/2019 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