Transcript 2012 Wexner Medical Center Template Getting Started in

The Placebo Response and Effect
 Can be significant
 30% or more in certain interventions
 An individual’s overall disease manifestation and
treatment outcome is influenced by one’s beliefs,
emotional and cognitive status and overall
feeling of well-being
 The placebo response occurs in patients with
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Chronic pain, sensory processing
Movement disorders and motor dysfunction
Behavior and mental disorders
Cognitive disorders
The Placebo Effect
 The effect is linked to expectation of
improvement, Pavlovian conditioning, and other
mechanisms
 Many neuromodulation studies have resulted in
failures when the treatment outcome is
compared to placebo
 Migraine, stroke, depression, Parkinson’s
gene infusion therapies
 Parkinson’s STN DBS study demonstrating
objective improvement in motor function with the
DBS OFF and suggestion to patient being ON
Placebo Effect in Chronic Pain
Neurochemical mechanisms
 Endogenous opioid system implicated
 The affect can be blocked and reversed by
the μ-opioid antagonist (Naloxone)
 Higher concentrations of endorphins in
in the CSF
 Autonomic connections
 Placebo analgesia is accompanied by
reduced heart rate and decreased βadrenergic responses
 Placebos can also act on 5-HTdependent hormone secretion
 Pituitary and adrenal glands
Placebo and Brain Imaging
 Increase in cerebral blood
flow in the rostral anterior
cingulate cortex
 Similar outcome as with
the administration of
opioid receptor agonist
(Remifentanil)
 (Petrovic et al).
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Placebo and Brain Imaging
 Modulation of the
 Insular cortex, thalamus, sensory cortex
 Pre-frontal cortex, DLPFC, Orbitofrontal cortex
 Similar regions are implicated in
 Chronic pain
 Anxiety, depression, behavior
 Brain regions activated by noxious stimuli
were diminished in placebo
 Benedetti, Wager, Amanzino, Levine
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Placebo and Study Trial Design
 Comparison to placebo control design
 Is the placebo control itself been validated as a
true control when there has been an intervention
 The neuromodulation implant, the close follow-up
monitoring and attention to patients can
potentially alter the natural course of the disease
and responsiveness
 Need more studies comparing neuromodulation
intervention to best medical management
 Blinding strategies may need to be modified
 Cross over design
 Longer-term blinded evaluations
 How about a non-invasive placebo stimulator as
the next big thing in neuromodulation
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Neuromodulation Patient Selection:
The Disease
 The Disease
 Complex disorders classified by a NAME
 However these are heterogeneous disorders with
pathophysiology, and clinical presentation
 Movement disorders, epilepsy, chronic pain, psychiatric and
cognitive disorders
 Subtypes and similar presentations are classified and
categorized under one disorders
 Dedicated team of specialists evaluating the patients to
verify
 Diagnosis accuracy and chronicity
 Co-morbidity variables
 Treatment resistance and severity
 Pre-morbid functional status
Neuromodulation Patient Selection:
The Chronic Refractory Condition
 Chronic disease and disability
 What is considered a disability and how is that determined
 Will that disability specifically improve with
neuromodulation
 PD-Posture, writing, speech will not improve
 Is the motor disability worse than the pain
 Often the most problematic and disabling element of the
disease may not be congruent with the symptoms
neuromodulation optimally treats
 Does the neurological examination make sense and correlate
with the anatomical lesion
 Severe tremor that stops with distraction
 Location of pain
Neuromodulation Patient Selection:
When is the right time for Neuromodulation
 When is the right time for neuromodulation implant
 What is a refractory patient
 What is an end stage patient
How many meds, how many procedures does the
patient need to have before being an “appropriate”
candidate
Is there a capacity and reserve in the neuronal network
to allow for neuromodulation to work optimally
 When do you consider neuromodulation intervention
 Early vs. late
Neuromodulation Patient Selection:
Previous treatments
 Previous history of response to medications or
treatments is a positive predictor
 Negative predictors
 A patient who gets worse with every procedure
 A patient whose pain migrates with each procedure
 Multiple procedures
 A patient had multiple complications and adverse events
with each procedure
Neuromodulation: Patient Selection
Neuropsychological Screening
Psychiatric evaluation
 No major untreated psychological factors
• Axis I-depression, anxiety, OCD must be controlled and stable
•Axis II—Caution--borderline personality
• dependence or gain
Pain
Depression
Stress
Limited/Loss of Abilities
Neuromodulation: Patient
Selection Variables
 Social elements
 Family and social support systems need to be in place
 Work situation
 Patient and family must be cooperative and motivated
Neuromodulation: Patient
Selection Variables
 Clear understanding of the procedure
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Benefits—SYMPTOMATIC and NOT A CURE
Complications must be very clearly understood and repeated
Realistic expectations about benefits need to be emphasized
Motivated to get better
Follow-up with therapy and neuromodulation implant adjustments
Neuromodulation: Patient
Selection Variables
 Adjunctive therapies are important
 Neuromodulation procedures is one part of an overall
integrated rehabilitation strategy
 Programming is complex and requires vigilance,
monitoring and expertise
 Disease fluctuations and progression need to be
considered
 Initiation of other therapies
 Social and occupational changes
 Adjustment to life change
Neuromodulation Patient Selection:
Biomarkers
 Biomarkers are important area of research and
necessity to improve patient selection
 Imaging
 Functional MRI, PET, EEG
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Blood test
Genetic screening
TMS
Other physiological markers
Neuromodulation: Patient Selection
Variables
 Neuromodulation can be very effective and improve
function and quality of life
 However patient selection is:
 Not trivial
 Need to consider many variables
 Evaluation
 Clear and detailed understanding of the patient
 Multidisciplinary team assessment
 Different time points
 Team meetings to agree on selection, discussing the
overall patient, social status, and follow-up care prior to
performing actual procedure
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