Ketamine Use in a Patient with Sickle Cell Crisis Refractory to Opiate Therapy Vatché Demirjian, PharmD PGY2 Drug Information Resident Rutgers University

Conflict of Interest Consultant for Haymarket Medical Education No other conflicts to disclose

Objectives Explain the epidemiology and pathophysiology of sickle cell crisis Develop a medication regimen that could be used to help treat patients in sickle cell crisis who may be refractory to opiates

Case History and Physical Admitted June 6, 2016 29 year old African American male Multiple ED admissions due to sickle cell crisis Avascular necrosis Extensive surgical history (including hip replacements) Requires a blood transfusion every three weeks Pain score 10

Case Outpatient Medications Hydromorphone 8 mg PO Q3 hrs PRN Morphine Extended Release 100 mg PO BID Diclofenac 100 mg PO BID Deferasirox 1000 mg PO QD Hydroxyurea 500 mg PO QD Folic acid 1 mg QD Lactulose PRN Pain score 10

Table 1. Sickle Cell Genotypes Sickle Cell Disease HbAS HbSS Inherited disorder (HbSS) 70,000 to 100,000 patients in the United States Disease modifying treatments Hydroxurea Blood Transfusions Most children survive into adulthood Sickle Cells have short half lives Complications: fever related to infection, acute kidney injury, acute anemia, stroke Carrier Table 1. Sickle Cell Genotypes Genotype Hb (g/dL) HbS (%) SS 6-9 >90 AS Normal <40% Yawn BP, Buchanan GR, Afenyi-Annan AN, et al. JAMA. 2014;312(10):1033-1048.

Sickle Cell Crisis Vaso-Occlusive Crisis (VOC) Tissue ischemia Musculoskeletal pain Variable intensity Sharp Stabbing Throbbing Unpredictable Leading cause of emergency room visits and admissions Yawn BP, Buchanan GR, Afenyi-Annan AN, et al. JAMA. 2014;312(10):1033-1048.

Pharmacological Options Our Patient Day 42 – Pain and Palliative Care following Methadone 15 mg TID Total daily IV dose of hydromorphone ___ _mg Possible Opioid Induced Hyperalgesia? Mild to Moderate Pain Acetaminophen NSAIDS Moderate – Severe Opiates (morphine sulfate, hydromorphone, fentanyl) Adjuvant Therapies for Neuropathic pain Anxiety Constipation Yawn BP, Buchanan GR, Afenyi-Annan AN, et al. JAMA. 2014;312(10):1033-1048. Uprety D, Baber A, Foy M. Annals Hematol. 2014. 93(5):769-71.

Assessment 1 VOC is a severe complication of sickle cell disease. Which of the following are characteristics of VOC? Tissue ischemia Predictable Vary in intensity I only I and II I and III II and III I, II and III

Literature Analysis

Medline MeSH Terms: - (1) Anemia, Sickle Cell [Complications, Drug therapy, Therapy] - (2) Ketamine [Administration & Dosage, Therapeutic Use] - (1) and (2) Relevant Results: 2

Medline The role of a low-dose ketamine-midazolam regimen in the management of severe painful crisis in patients with sickle cell disease. J Pain Symptom Manag. 2014. Ketamine infusion for sickle cell pain crisis refractory to opioids: a case report and review of literature. Ann. Hematol. 2014. MeSH Terms: - (1) Anemia, Sickle Cell [Complications, Drug therapy, Therapy] - (2) Ketamine [Administration & Dosage, Therapeutic Use] - (1) and (2) Relevant Results: 2

Study 1 – Uprety et al. 31 y/o AA male presented to emergency department with chest tightness, significant joint pain, and headache for 1 week Medications: Methadone 80 mg PO TID Oxycodone 120 mg PO q 3 hours as needed for pain control. Pain score was still 10/10 despite increase in opioids Day 30: Pain and Palliative Care team – opioid induced hyperalgesia Administered ketamine Result: Ketamine Day 7, pain score decreased significantly ranging to 4-6 out of 10 Uprety D, Baber A, Foy M. Ann Hematol. 2014. 93(5):769-71.

Morphine IV requirement Study 2 – Tawfiq QA et al. Retrospective chart review Patients who were not responding to morphine Ketamine/midazolam added to patients refractory to opioids. Day Morphine IV requirement 145.6 mg +/- 16.5 mg 1 112 mg +/- 12.2 mg p = 0.007 Tawfic QA, Faris AS, Kausalya R. J Pain Symptom Manag. 2014. 47(2): 334-340.

Study 2 – Tawfiq QA et al. Regimen: Ketamine bolus 0.25 mg/kg Ketamine infusion 0.2-0.25 mg/kg/hr Midazolam bolus 1 mg Midazolam infusion 0.5-1 mg/hr Conclusion: Low dose ketamine might be effective in lowering opiate requirements in addition to providing pain relief. Tawfic QA, Faris AS, Kausalya R. J Pain Symptom Manag. 2014. 47(2): 334-340.

Ketamine FDA Indications: General anesthesia, procedural sedation, rapid sequence intubation Mechanism of Action: Nonbarbituate anesthetic and analgesic agent. Used in outpatient and inpatient surgical procedures Adverse effects: Respiratory depression, cardiovascular effects, emergence reactions Ketalar ® [Package insert]. JHP Pharmaceuticals, LLC. Rochester, MI [Updated 2012 March; Cited 2017 Feb 023]. Ketamine (electronic version). Truven Health Analytics, Greenwood Village, Colorado, USA. Available at: http://www.micromedexsolutions.com/ (cited: 2/28/2017).

Ketamine ADME Outcome Absorption (Onset) 20-40 seconds Distribution Protein Binding 47% Volume of Distribution 2 to 3 L/kg Metabolism Liver (extensive) Metabolite: Norketamine (active) Elimination 12 to 17 mL/minute/kg Ketalar ® [Package insert]. JHP Pharmaceuticals, LLC. Rochester, MI [Updated 2012 March; Cited 2017 Feb 023]. Ketamine (electronic version). Truven Health Analytics, Greenwood Village, Colorado, USA. Available at: http://www.micromedexsolutions.com/ (cited: 2/28/2017).

Assessment When administering ketamine IV infusion for analgesia, it is important to add _____________ in an effort to decrease the risk of ketamine induced __________. Norepinephrine; hypoperfusion Benzodiazepines; emergence reactions Benzodiazepines; respiratory depression BiPAP; emergence reactions

Consultation with Physician Original Question: Is ketamine a potential medication therapy for a patient in sickle cell crisis? Current Regimen: Hydromorphone 1 mg/hr and clinician bolus 4 mg IV Q 3 hr PRN Methadone PO Q8 hrs (25 mg at 8 am and 4 pm) and 30 mg PO at 10 pm Dexamethasone 4 mg PO Q12 Indomethacin 25 mg PO TID Pregabalin 100 mg PO Q8

Consultation with Physician Original Question: Is ketamine a potential medication therapy for a patient in sickle cell crisis? Our Recommendation Yes Ketamine bolus 0.25 mg/kg Ketamine infusion 0.2-0.25 mg/kg/hr Midazolam bolus 1 mg Midazolam infusion 0.5-1 mg/hr Duration maximum 7 days, then decrease by 25% Q 24 hours.

Total Daily Dose of IV Hydromorphone Outcome Ketamine (0.25mg/kg/hr) Day Total Daily Dose of IV Hydromorphone (last 24 hours) Pain Score (Ketamine bolus 0.25mg/kg x 1) 124 mg 10 7 85 mg 5 62.7 mg 4 12 45 mg 14 Ketamine Stopped 28 mg

Conclusion Ketamine is a potential therapeutic option for patients in sickle cell crisis who are refractory to opiates. Bolus plus continuous infusion is reasonable Add benzodiazepine for reduction in emergence reactions

References Tawfic QA, Faris AS, Kausalya R. The role of a low-dose ketamine-midazolam regimen in the management of severe painful crisis in patients with sickle cell disease. J Pain Symptom Manage. 2014; 47(2):334-40. Uprety D, Baber A, Foy M. Ketamine infusion for sickle cell pain crisis refractory to opioids: a case report and review of literature. Ann Hematol. 2014; 93(5):769-71. 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):1033-48.