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Wally R. Smith, MD Professor, Division of General Internal Medicine Principal Investigator VCU Basic and Translational Research Program in Sickle Cell.

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Presentation on theme: "Wally R. Smith, MD Professor, Division of General Internal Medicine Principal Investigator VCU Basic and Translational Research Program in Sickle Cell."— Presentation transcript:

1 Wally R. Smith, MD Professor, Division of General Internal Medicine Principal Investigator VCU Basic and Translational Research Program in Sickle Cell Disease VCU Sickle Cell Disease Outcomes Research Center, SCD Clinical Research Network Scientific Director VCU Center on Health Disparities Sickle Cell and Pain Management: A New Era

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3 Chronic Palliative/Symptomatic Therapy FolateFolate Opioids--Short and long-actingOpioids--Short and long-acting Non-steroidals, other analgesicsNon-steroidals, other analgesics Local therapyLocal therapy –Heat –Massage –TENS Coping, psychosocial, holistic interventionsCoping, psychosocial, holistic interventions Case managementCase management

4 Smith’s Hypotheses Pain phenotype transformation to mixed phenotypePain phenotype transformation to mixed phenotype –in some patients –From acute-on-chronic, multi-local inflammatory pain –to also central and/or peripheral neuropathic pain –due to acute-on-chronic vaso-occlusion, inflammation, and ischemia, resulting in central or local neuronal damage –A threshold of ischemic necrosis of neurons, before phenotype transformation SCD ischemic neuropathy may share common mechanisms with other neuropathic pain syndromesSCD ischemic neuropathy may share common mechanisms with other neuropathic pain syndromes Opioid, non-opioid chemical, and other approaches may improve pain in SCDOpioid, non-opioid chemical, and other approaches may improve pain in SCD By far, the best approach to SCD pain is interruption of sickle cell vasculopathy in childhoodBy far, the best approach to SCD pain is interruption of sickle cell vasculopathy in childhood

5 Nociceptive Pain a noxious stimulus-detecting sensory system. …an alarm mediated by high-threshold …primary sensory neurons that feed into nociceptive pathways of the central nervous system …. tuned to respond to intense thermal or mechanical stimuli as well as exogenous and endogenous chemical mediators –Costigan M, Scholz J, Woolf CJ. Neuropathic pain: a maladaptive response of the nervous system to damage. Annu Rev Neurosci. 2009;32:1-32. Review. PubMed PMID: ; PubMed Central PMCID: PMC

6 Inflammatory Pain This pain occurs in response to tissue injury and the subsequent inflammatory response. Here the imperative shifts from protecting the body against a potentially damaging noxious stimulus to addressing the consequences of damage. To aid healing and repair of the injured body part, the sensory nervous system undergoes a profound change in its responsiveness; normally innocuous stimuli now produce pain and responses to noxious stimuli are both exaggerated and prolonged. –Costigan M, Scholz J, Woolf CJ. Neuropathic pain: a maladaptive response of the nervous system to damage. Annu Rev Neurosci. 2009;32:1-32. Review. PubMed PMID: ; PubMed Central PMCID: PMC

7 The Neuropathic Pain Phenotype After nerve injury maladaptive changes can occur in injured sensory neurons and along the entire nociceptive pathway within the CNS, which may lead to spontaneous pain or pain hypersensitivity. The resulting neuropathic pain syndromes present as a complex combination of negative and positive symptoms, which vary enormously from individual to individual. This variation depends on a diversity of underlying pathophysiological changes resulting from the convergence of etiological, genotypic, and environmental factors.After nerve injury maladaptive changes can occur in injured sensory neurons and along the entire nociceptive pathway within the CNS, which may lead to spontaneous pain or pain hypersensitivity. The resulting neuropathic pain syndromes present as a complex combination of negative and positive symptoms, which vary enormously from individual to individual. This variation depends on a diversity of underlying pathophysiological changes resulting from the convergence of etiological, genotypic, and environmental factors. The pain phenotype can serve therefore, as a window on underlying pathophysiological neural mechanisms and as a guide for developing personalized pain medicine.The pain phenotype can serve therefore, as a window on underlying pathophysiological neural mechanisms and as a guide for developing personalized pain medicine. –1: von Hehn CA, Baron R, Woolf CJ. Deconstructing the neuropathic pain phenotype to reveal neural mechanisms. Neuron Feb 23;73(4): Review. PubMed PMID: ; PubMed Central PMCID: PMC

8 Pain Phenotype Transition in SCD

9 Smith’s Hypotheses—Level of Support 1.Sickle cell pain may in some patients transform from purely acute-on-chronic, multi-local inflammatory pain to also central and/or peripheral neuropathic pain (phenotype transformation) 2.The phenotype transformation occurs due to acute- on-chronic vaso-occlusion, inflammation, and ischemia, resulting in central or local neuronal damage 3.A threshold of ischemic necrosis of neurons must be reached, likely during late childhood, before phenotype transformation in SCD 4.Sickle cell disease ischemic neuropathy may share common mechanisms with other neuropathic pain syndromes 5.Phenotype transformation manifests as both inflammatory pain and neuropathic pain—a mixed phenotype 6.Thus, opioid, non-opioid chemical, and other approaches may improve pain in SCD 7.Opioid-induced hyperalgesia is a minor component of pain in SCD 8.By far, the best approach to SCD pain is interruption of sickle cell vasculopathy in childhood 1 Pain chronicity manifests over time 1 Etiology of chronic pain not etiologically distinguishable using current data (1 study) 1, 2,3 Acute pain fluctuations continue throughout life, supporting. 4-Pain Locations multiple, somewhat bilateral, pain descriptors often neuropathic 5-No data 6-Weak, correlational support for 6a 7-Data not conclusive-correlational 8-Rel’.of sev. of SCD pain to sev. of vasculopathy (response to HU, transplantation, geography of residence, and seasonal temperature/climate changes).

10 Above water Submerged Pain Intensity On Crisis Vs Non- crisis Vs. Utilization Days *Percentage of days. Utilization= utilization with or without crisis or pain; Crisis= crisis without utilization; Pain= pain without crisis or utilization Adapted from Smith WR, et. al. Ann Intern Med 2008 Jan 15, 148(2): % 44.1% 13.1% 3.5% Intensity Mean Std Dev Utilization Crisis w/o utilization Pain w/o crisis, util No Pain 0 0

11 Acute Nociceptive, Inflammatory Pain Likely Hierarchy of Sub Biologies Acute sickling Acute deoxygenation Acute Temperature change (cold climate, wind speed) Barometric pressure change Oxygen delivery change (infection, other) Acute Hemolysis, free Hb, NO depletion Acute Vaso- occlusion, ischemia CHRONIC PAIN Acute Vaso- constriction Acute inflammation, Acute inflammation, Fig. (1). Probable hierarchy of the major sub-biologies participating in development of sickle vasculopathy. Modified from Kato GJ, Hebbel RP, Steinberg MH, Gladwin MT; Vasculopathy in Sickle Cell Disease: Biology, pathophysiology, genetics, translational medicine and new research directions. [Meeting Report] Am. J. Hematol., Reperfusion Injury Physiology Inflammation Macrophage & immune Activation Oxidant generation NO depletion Coagulation activation Endothelial activation Vascular stasis RBC sickling Hemolysis, Chronic Nociceptive, Inflammatory Pain Likely Hierarchy of Sub Biologies ENVIRONMENTAL SYSTEMS BIOLOGY ACUTE PAIN Acute sickling SYSTEMS BIOLOGY

12 Contributors to Inflammation of SCD ↑ number of granulocytes & monocytes in blood↑ number of granulocytes & monocytes in blood ↑ activation of granulocytes and monocytes↑ activation of granulocytes and monocytes activated phenotype of circulating endothelial cells (pro-adhesive, procoagulant, pro-oxidative)activated phenotype of circulating endothelial cells (pro-adhesive, procoagulant, pro-oxidative) ↑ soluble VCAM and P-selectin↑ soluble VCAM and P-selectin activation of the coagulation systemactivation of the coagulation system ↑ levels of inflammatory mediators (e.g., IL6, CRP, TNFα, IL1β)↑ levels of inflammatory mediators (e.g., IL6, CRP, TNFα, IL1β) ↑ levels of acute phase reactants (e.g., CRP, phospholipase-A2, ferritin)↑ levels of acute phase reactants (e.g., CRP, phospholipase-A2, ferritin) ↑ levels of endothelial cell perturbants *↑ levels of endothelial cell perturbants * ↑ microparticles from monocytes, platelets, endothelial cells, red cells. sickle mice have an inflammatory state↑ microparticles from monocytes, platelets, endothelial cells, red cells. sickle mice have an inflammatory state –* which include, but are not limited to: hypoxia, thrombin, IL2, IL4, IL8, endotoxin,TGFβ, thrombospondin, G-CSF, GM-CSF,endothelin-1, 12-HETE, peroxynitrite, serum amyloid a, PGE2, fibrinogen, leukotriene B4, homocysteine, CD40 Ligand Robert P. Hebbel, Greg M. Vercellotti and Karl A. Nath. A Systems Biology Consideration of the Vasculopathy of Sickle Cell Anemia: The Need for Multi-Modality Chemo-Prophylaxis. Cardiovascular & Haematological Disorders-Drug Targets, 2009, 9, Robert P. Hebbel, Greg M. Vercellotti and Karl A. Nath. A Systems Biology Consideration of the Vasculopathy of Sickle Cell Anemia: The Need for Multi-Modality Chemo-Prophylaxis. Cardiovascular & Haematological Disorders-Drug Targets, 2009, 9,

13 Replacement By Donor Derived Red Cells Allows Tapering Of Opioids Takes weeksTakes weeks –Data, courtesy Tisdale, et al.

14 Pain Locations in PiSCES 201 subjects had:201 subjects had: – more than 5 days with pain >0 – body locator boxes endorsed 15,563 patient-days of body locator chart information analyzed15,563 patient-days of body locator chart information analyzed On these days:On these days: –an average of 11.3% of boxes were checked (analyses of % boxes checked not shown)(analyses of % boxes checked not shown) –an average of 3.3 of 16 sites (21%) were painful

15 No Association of Predominant Bilaterality With: GenderGender AgeAge GenotypeGenotype –SS vs SC Calendar SeasonsCalendar Seasons –Warm (April-Sept) vs Cold (Oct- March) seasons Although intensity of pain and frequency of pain higher in colder monthsAlthough intensity of pain and frequency of pain higher in colder months

16 Mean Pain Intensity on Pain Days (SD)* Percent Pain Days (SD) (1.5)81.9 (25.4) 4.1 (1.4)51.9 (35.3) 3.0 (1.2)16.8 (23.3) 2.8 (2.0)12.3 (30.9)  LA=long-acting, SA=Short- acting.  *Mean pain on pain days, overall ANOVA p<  All paired comparisons statistically significant except none vs non-opioid and none vs SA opioid.  + Percent pain days, overall ANOVA p<  All paired comparisons statistically significant except none vs. non-opioid Relationship of Pain to Opioid Use Fewer (38.8%) used LA opioids (w or w/o other analg’s) than used SA (47.0% w or w/o non-opioids)Fewer (38.8%) used LA opioids (w or w/o other analg’s) than used SA (47.0% w or w/o non-opioids) 9.6% only non-opioid, 4.6% none analgesics9.6% only non-opioid, 4.6% none analgesics Pain intens, freq higher with LA or higher total opioidPain intens, freq higher with LA or higher total opioid

17 Opioid Use and SCD Lab, Pain Complications N Number (%) of subjects who use opioids (n=188) Number (%) of subjects who do not use opioids (n=31) p-value comparing opioid users and non-users Hydroxyurea user Yes 5958 (98.3)1 (1.7) No (81.2)30 (18.8) Ankle Ulcers Yes (92.3) 2 ( 7.7) No (85.4)28 (14.6) Avascular Necrosis Yes (93.7) 3 ( 6.3) No (84.1)27 (15.9) Priapism (males only) Yes (86.7) 2 (13.3) No (85.3) 10 (14.7) Lab values (means)N Mean (SD) for opioid user Mean (SD) for those not using opioid P value comparing opioid users and non-users %Fetal Hemoglobin (7.2) 4.1 (7.3) White Blood Count (4.5)10.5 (4.3)

18 Pain Management in SCD: The New Era HydroxyureaHydroxyurea Non-opioid neuropathic agentsNon-opioid neuropathic agents Anti-sickling medicationsAnti-sickling medications –Anti-inflammatories/Selectin Inhibitors –Amino Acids –Platelet inhibitors –Hb-O2 Covalent Binders

19 Hydroxyurea Only FDA approved anti-sickling medicationOnly FDA approved anti-sickling medication It helps make fetal hemoglobin (Hb F, baby’s hemoglobin) within the red cellsIt helps make fetal hemoglobin (Hb F, baby’s hemoglobin) within the red cells This stops abnormal hemoglobin strands, decreases sicklingThis stops abnormal hemoglobin strands, decreases sickling Hydroxyurea makes the red cells healthierHydroxyurea makes the red cells healthier 50% reduction in hospitalization50% reduction in hospitalization 40% improved mortality40% improved mortality Also drops the white blood cell countAlso drops the white blood cell count –Major side effect –Sometimes too low

20 Hydroxyurea –approved for SCD 1996 Ribonucleotide reductase inhibitorRibonucleotide reductase inhibitor Reduces cell division during S- phaseReduces cell division during S- phase Inhibits RNA and protein synthesisInhibits RNA and protein synthesis Metabolized to genotoxic productsMetabolized to genotoxic products –Potential for adverse effects Timson J. Hydroxyurea. Mutat Res 1975; 32(2): Timson J. Hydroxyurea. Mutat Res 1975; 32(2):

21 Hydroxyurea-- Reduction in: –Acute painful episodes –Acute chest syndrome events –Hospitalizations –Blood transfusions Charache S, Terrin ML, Moore RD, Dover GJ, McMahon RP, Barton FB et al. Design of the multicenter study of hydroxyurea in sickle cell anemia. Controlled Clin Trials 1995; 16: Charache S, Terrin ML, Moore RD, Dover GJ, McMahon RP, Barton FB et al. Design of the multicenter study of hydroxyurea in sickle cell anemia. Controlled Clin Trials 1995; 16: Charache S, Terrin ML, Moore RD, Dover GJ, Barton FB, Eckert SV et al. Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia. N Engl J Med 1995; 332: Charache S, Terrin ML, Moore RD, Dover GJ, Barton FB, Eckert SV et al. Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia. N Engl J Med 1995; 332: –Costs of care Moore RD, Charache S, Terrin ML, Barton FB, Ballas SK, Investigators of the MUlticenter Study of Hydroxyurea in Sickle cell Anemia. Cost-effectiveness of hydroxyurea in sickle cell anemia. Am J Hematol 2000; 64:26-31.Moore RD, Charache S, Terrin ML, Barton FB, Ballas SK, Investigators of the MUlticenter Study of Hydroxyurea in Sickle cell Anemia. Cost-effectiveness of hydroxyurea in sickle cell anemia. Am J Hematol 2000; 64:26-31.

22 Hydroxyurea: Increase in: Fetal hemoglobin (HbF)Fetal hemoglobin (HbF) –Steinberg MH, Lu Z-H, Barton FB, Terrin ML, Charache S, Dover GJ et al. Fetal hemoglobin in sickle cell anemia: Determinants of response to hydroxyurea. Blood 1997; 89: Physical capacityPhysical capacity –Hackney AC, Hezier W, Gulledge TP, Jones S, Strayhorn D, Busby M et al. Effects of hydroxyurea administration on the body weight, body composition and exercise performance of patients with sickle-cell anaemia. Clin Sci 1997; 92: Quality of lifeQuality of life –Ballas SK, Barton FB, Waclawiw MA, Swerdlow P, Eckman JR, Pegelow CH et al. Hydroxyurea and sickle cell anemia: effect on quality of life. Health Qual Life Outcomes 2006; 4:59. Survival (40% reduction in mortality)Survival (40% reduction in mortality) –Steinberg MH, Barton F, Castro O, Pegelow CH, Ballas SK, Kutlar A et al. Effect of hydroxyurea on mortality and morbidity in adult sickle cell anemia: risks and benefits up to 9 years of treatment. Jama 2003; 289(13):

23 Ship HU Enhancing Use of Hydroxyurea in Sickle Cell Disease Using Patient Navigators  R18HL  Funded by National Heart Lung and Blood Institute  Sept 2012-June 2017

24 What does “Ship HU” Mean? What does “Ship HU” Mean? Start healing in patients with hydroxyurea Start healing in patients with hydroxyurea Stop hemolysis in patients with hydroxyurea Stop hemolysis in patients with hydroxyurea Stop hurting in patients with hydroxyurea Stop hurting in patients with hydroxyurea

25 SHIP HU: Specific Aim 1 Demonstrate the feasibility of a patient navigator- based program to improve the percentage of adult (age 15 and older) patients with sickle cell disease (SCD) in the Richmond and Tidewater regions of Virginia who are in SCD specialty care. Demonstrate the feasibility of a patient navigator- based program to improve the percentage of adult (age 15 and older) patients with sickle cell disease (SCD) in the Richmond and Tidewater regions of Virginia who are in SCD specialty care.

26 SHIP HU: Specific Aim 2 Demonstrate the effectiveness of a patient navigator- based program to improve hydroxyurea (HU) (re-) initiation and adherence among adult patients with SCD in the Richmond and Tidewater regions of Virginia who are eligible for HU. Demonstrate the effectiveness of a patient navigator- based program to improve hydroxyurea (HU) (re-) initiation and adherence among adult patients with SCD in the Richmond and Tidewater regions of Virginia who are eligible for HU.

27 Overall Justification of Ship HU Hydroxyurea (HU) may be life- saving and should be given to eligible SCD patients.Hydroxyurea (HU) may be life- saving and should be given to eligible SCD patients. Specialists prescribe Hydroxyurea to SCD patientsSpecialists prescribe Hydroxyurea to SCD patients Large % SCD patients not in SCD specialty care, barriers to care.Large % SCD patients not in SCD specialty care, barriers to care.

28 What is a Patient Navigator? Lay member of a communityLay member of a community –works either for pay or as a volunteer in association with the local health care system. –shares ethnicity, language, socioeconomic status, and life experiences with community members. –links community members to the medical care system, provide social networking, social support, and personalized interventions Other termsOther terms –Community Health Advisor, Lay Health Advocate, Promotor, Outreach Educator, Community Health Representative, Peer Health Promoter, or Peer Counselor

29 Planned Journey of Ship HU Address barriers to care and to HU useAddress barriers to care and to HU use Two-phase demonstrationTwo-phase demonstration –Improvement in the % with SCD who are in SCD specialty care (Phase I) –Improvement in adherence to HU of eligible SCD adults (Phase II). Use existing health apparatusUse existing health apparatus –State of Virginia (VDH), two academic med. Ctr’s Use specially trained SCD patient navigators (PNs)Use specially trained SCD patient navigators (PNs)

30 Ship HU: Participating Providers Two adult, two pediatric specialty clinicsTwo adult, two pediatric specialty clinics –VCU Pediatric clinic (15 and older)Pediatric clinic (15 and older) Adult Clinic (17 and older)Adult Clinic (17 and older) –EVMS/CHKD CHKD (15 and older, including Oyster Point clinic)CHKD (15 and older, including Oyster Point clinic) EVMS (17 and older)EVMS (17 and older)

31 Interventions to Alter Health Behaviors Enviromental Setting Macro-Level Sectors of Influence Institutions Patient-Clinician Relationship Social Networks Individual Factors Biopyschosocial spriritual InterventionTarget Law/Policy ChangeEnvironmental Setting AdvertisingMacro-level Sectors of influence Health Fair, Build Clinic, change clinic operations Institutions Hire Doctor or Navigator Patient-Clinician Relationship Family or church intervention, Facebook Social Networks One-to-one counseling (from Navigator, anyone), Rx Individual Factors

32 Template for Regional Recruitment Strategy InterventionTargetExpected BenefitsImmediate Recruitment Results Advertising (Radio, newspaper, fliers, etc.) Macro-level influenceAwareness Reach the “tipping point” Find partners Generate recruitment leads Low Health FairsInstitutionsAwareness Reach the “tipping point” Find partners Generate recruitment leads Low Presentations, EventsInstitutions, patient social networks Awareness Find partners Generate recruitment leads Recruit Medium Navigator calls, followup of leads Social networks (of navigators) Find partners Generate recruitment leads Recruit Medium ED and Clinic RecruitmentSocial networks (of patients)Generate recruitment leads Recruit High Church interventionsSocial Networks (of patients)Generate recruitment leads Recruit Medium to high Electronic Pre-screening (Medicaid, Health Dept Records) IndividualsRecruitHigh

33 Ways ODMS can help Ship HU Help identify clients and assist with recruitment into our study Help identify clients and assist with recruitment into our study –Send a letter to your patients on your letterhead with study details. –Organize recruiting events at which Ship HU staff could speak. –Tips to Ship HU staff about how best to reach clients. –Letters of support or other endorsements to organizations and media outlets who may advertise our study or refer clients.


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