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Sickle Cell and Pain
Management: A New Era
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
Chronic Palliative/Symptomatic
Therapy
•
•
•
•
Folate
Opioids--Short and long-acting
Non-steroidals, other analgesics
Local therapy
– Heat
– Massage
– TENS
• Coping, psychosocial, holistic
interventions
• Case management
Smith’s Hypotheses
• Pain 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
syndromes
• Opioid, 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 childhood
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: 19400724; PubMed Central PMCID:
PMC2768555.
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: 19400724; PubMed Central
PMCID: PMC2768555.
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.
• 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. 2012 Feb
23;73(4):638-52. Review. PubMed PMID: 22365541; PubMed Central PMCID: PMC3319438.
Pain Phenotype Transition in
SCD
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 acuteon-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).
Pain Intensity On Crisis Vs Noncrisis Vs. Utilization Days
Intensity
Above
water
Submerged
Utilization
6.5
2.3
Crisis w/o utilization 5.5
2.1
3.5%
13.1%
39.3%
44.1%
Mean Std
Dev
Pain w/o crisis, util.
No Pain
*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):94-101
4.2
2
0
0
Acute Nociceptive, Inflammatory Pain Likely Hierarchy of Sub Biologies
ENVIRONMENTAL
Acute Temperature
change (cold climate,
wind speed)
Barometric pressure
change
Oxygen delivery
change (infection,
other)
SYSTEMS BIOLOGY
Acute
Hemolysis,
free Hb, NO
depletion
Acute
deoxygenation
Acute Vasoconstriction
Acute
sickling
Acute Vasoocclusion,
ischemia
Acute
sickling
ACUTE
PAIN
Chronic Nociceptive, Inflammatory Pain Likely Hierarchy of Sub Biologies
SYSTEMS BIOLOGY
Macrophage &
immune Activation
Hemolysis,
Oxidant generation
Reperfusion
Injury
Physiology
NO depletion
Inflammation
Coagulation
activation
Endothelial activation
RBC
sickling
CHRONIC
PAIN
Vascular
stasis
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., 2009.
Contributors to Inflammation of SCD
• ↑ number of granulocytes & monocytes in blood
• ↑ activation of granulocytes and monocytes
• activated phenotype of circulating endothelial cells (pro-adhesive,
procoagulant, pro-oxidative)
• ↑ soluble VCAM and P-selectin
• activation of the coagulation system
• ↑ levels of inflammatory mediators (e.g., IL6, CRP, TNFα, IL1β)
• ↑ levels of acute phase reactants (e.g., CRP, phospholipase-A2, ferritin)
• ↑ levels of endothelial cell perturbants *
• ↑ 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, 271-292
Replacement By Donor Derived Red
Cells Allows Tapering Of Opioids
IV morphine equivalent (mg)
2000
1600
1200
800
400
0
0
4
8
12
16
Takes weeks
– Data, courtesy Tisdale, et al.
Weeks
20
24
28
Pain Locations in PiSCES
• 201 subjects had:
– more than 5 days with pain >0
– body locator boxes endorsed
• 15,563 patient-days of body locator
chart information analyzed
• On these days:
– an average of 11.3% of boxes were checked
• (analyses of % boxes checked not shown)
– an average of 3.3 of 16 sites (21%) were painful
No Association of
Predominant Bilaterality With:
• Gender
• Age
• Genotype
– SS vs SC
• Calendar Seasons
– Warm (April-Sept) vs Cold (OctMarch) seasons
• Although intensity of pain and frequency of pain
higher in colder months
Relationship of Pain to Opioid Use
100%
Mean Pain
Intensity on
Pain Days (SD)*
85
90%
Percent Pain
Days (SD)+
80%
70%
60%
LA opioid (+/any analgesic) 4.8 (1.5)
81.9 (25.4)
SA opioid (+/non-opioid)
4.1 (1.4)
51.9 (35.3)
Non-opioid
only
3.0 (1.2)
16.8 (23.3)
None
2.8 (2.0)
12.3 (30.9)
103
50%
40%
30%
20%
10%
21
0%
10
Patients
LA=long-acting, SA=Shortacting.
*Mean pain on pain days,
overall ANOVA p<0.0001.
All paired comparisons
statistically significant
except none vs non-opioid
and none vs SA opioid.
+ Percent pain days, overall
ANOVA p<0.0001.
All paired comparisons
statistically significant
except none vs. non-opioid
• 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 analgesics
• Pain intens, freq higher with LA or higher total opioid
Opioid Use and SCD Lab, Pain
Complications
N
Hydroxyurea user
Yes
59
No
160
Ankle Ulcers
Yes
26
No
192
Avascular Necrosis
Yes
48
No
170
Priapism (males only)
Yes
No
Lab values (means)
%Fetal Hemoglobin
White Blood Count
Number (%) of
subjects who use
opioids (n=188)
Number (%) of
subjects who do not
use opioids (n=31)
58 (98.3)
130 (81.2)
1 (1.7)
30 (18.8)
p-value comparing
opioid users and
non-users
0.0013
0.3385
24 (92.3)
164 (85.4)
2 ( 7.7)
28 (14.6)
0.0871
45 (93.7)
143 (84.1)
3 ( 6.3)
27 (15.9)
0.8912
15
68
N
13 (86.7)
58 (85.3)
Mean (SD) for
opioid user
2 (13.3)
10 (14.7)
Mean (SD) for those
not using opioid
180
158
3.9 (7.2)
11.2 (4.5)
4.1 (7.3)
10.5 (4.3)
P value comparing
opioid users and
non-users
0.8955
0.4913
Pain Management in SCD:
The New Era
• Hydroxyurea
• Non-opioid neuropathic agents
• Anti-sickling medications
– Anti-inflammatories/Selectin Inhibitors
– Amino Acids
– Platelet inhibitors
– Hb-O2 Covalent Binders
Hydroxyurea
• Only FDA approved anti-sickling medication
• It helps make fetal hemoglobin (Hb F, baby’s
hemoglobin) within the red cells
• This stops abnormal hemoglobin strands, decreases
sickling
• Hydroxyurea makes the red cells healthier
• 50% reduction in hospitalization
• 40% improved mortality
• Also drops the white blood cell count
– Major side effect
– Sometimes too low
Hydroxyurea –approved for
SCD 1996
• Ribonucleotide reductase inhibitor
• Reduces cell division during Sphase
• Inhibits RNA and protein synthesis
• Metabolized to genotoxic products
– Potential for adverse effects
• Timson J. Hydroxyurea. Mutat Res 1975;
32(2):115-132.
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; 16:432-446.
• 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; 332:1317-1322.
– 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.
Hydroxyurea: Increase in:
• 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; 89:1078-1088.
• Physical 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;
92:481-486.
• Quality 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)
– 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):16451651.
Ship HU
Enhancing Use of Hydroxyurea in Sickle
Cell Disease Using Patient Navigators
 R18HL112737
 Funded by
National Heart
Lung and Blood
Institute
 Sept 2012-June
2017
What does “Ship HU” Mean?
 Start healing in patients with hydroxyurea
 Stop hemolysis in patients with
hydroxyurea
 Stop hurting in patients with hydroxyurea
SHIP HU: Specific Aim 1
 Demonstrate the feasibility of a patient navigatorbased 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.
SHIP HU: Specific Aim 2
 Demonstrate the effectiveness of a patient navigatorbased 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.
Overall Justification of Ship HU
• Hydroxyurea (HU) may be lifesaving and should be given to
eligible SCD patients.
• Specialists prescribe Hydroxyurea
to SCD patients
• Large % SCD patients not in SCD
specialty care, barriers to care.
What is a Patient
Navigator?
• Lay 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 terms
– Community Health Advisor, Lay Health
Advocate, Promotor, Outreach Educator,
Community Health Representative, Peer
Health Promoter, or Peer Counselor
Planned Journey of Ship HU
• Address barriers to care and to HU use
• Two-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 apparatus
– State of Virginia (VDH), two academic med. Ctr’s
• Use specially trained SCD patient navigators
(PNs)
Ship HU: Participating Providers
• Two adult, two pediatric specialty
clinics
– VCU
• Pediatric clinic (15 and older)
• Adult Clinic (17 and older)
– EVMS/CHKD
• CHKD (15 and older, including Oyster Point
clinic)
• EVMS (17 and older)
Interventions to Alter Health Behaviors
Intervention
Target
Law/Policy Change
Environmental
Setting
Enviromental Setting
Advertising
Macro-level Sectors
of influence
Macro-Level Sectors
of Influence
Health Fair, Build
Clinic, change clinic
operations
Institutions
Hire Doctor or
Navigator
Patient-Clinician
Relationship
Family or church
Social Networks
intervention, Facebook
One-to-one counseling Individual Factors
(from Navigator,
anyone), Rx
Institutions
Patient-Clinician
Relationship
Social
Networks
Individual Factors
Biopyschosocial
spriritual
Template for Regional
Recruitment Strategy
Intervention
Target
Expected Benefits
Immediate
Recruitment
Results
Advertising (Radio,
newspaper, fliers, etc.)
Macro-level influence
•
•
•
•
Awareness
Reach the “tipping point”
Find partners
Generate recruitment leads
Low
Health Fairs
Institutions
•
•
•
•
Awareness
Reach the “tipping point”
Find partners
Generate recruitment leads
Low
Presentations, Events
Institutions, 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 Recruitment
Social networks (of patients)
• Generate recruitment leads
• Recruit
High
Church interventions
Social Networks (of patients)
• Generate recruitment leads
• Recruit
Medium to high
Electronic Pre-screening
(Medicaid, Health Dept
Records)
Individuals
• Recruit
High
Ways ODMS can help Ship HU
• Help identify clients and assist with recruitment into our
study.
800-828-6938
– 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.