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 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 β- adrenergic responses

Placebos can also act on 5-HT-dependent hormone secretion

Pituitary and adrenal glands

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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 presentationMovement disorders, epilepsy, chronic pain, psychiatric and

cognitive disordersSubtypes and similar presentations are classified and

categorized under one disorders Dedicated team of specialists evaluating the patients to

verifyDiagnosis accuracy and chronicity Co-morbidity variablesTreatment resistance and severityPre-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 evaluationNo major untreated psychological factors

Pain

Stress

Depression

Limited/Loss of Abilities

• Axis I-depression, anxiety, OCD must be controlled and stable•Axis II—Caution--borderline personality• dependence or gain

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 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 Blood test Genetic screening TMS Other physiological markers

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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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