Document text
Principal Investigator: Charles Chiedu Nwaokobia
Organization: EVON MEDICS, LLC
Fiscal Year: 2024
Award: $1,349,130
Funding agency: National Institute of Neurological Disorders and Stroke
PHASE I/II (FAST/TRACK) ABSTRACT
The Development and Evaluation of Computerized Chemosensory-Based Orbitofrontal Networks
Training for Treatment of Pain (CBOT-P) is a project to develop an effective, scalable, user-friendly, and home-
based neuromodulatory platform for broad-spectrum treatment of chronic pain conditions with associated
negative affect and cognitive impairments. Chronic pain (CP) affects 1.5 billion people globally, and causes
severe human suffering, disability, and high financial burden. Clinical and neuroscience studies show that CP
over time leads to shrinkage in the prefrontal cortex (PFC) regions and their deep brain connections critical to
emotion, motivation, and cognitive functions. As a result, more than 40% of CP patients suffer negative affect
(i.e., anxiety and depression), cognitive and decision-making problems and reduced drive. Chronic pain with
negative affect (CP-N) is more debilitating, harder to treat, costlier to payers and significantly more associated
with opioid use, overdose, and deaths. In a stakeholder value canvassing exercise CP sufferers and pain
doctors unanimously desire new non-invasive, home-based, safe, and effective interventions that can reduce
pain severity by more than 10%, suggesting that current treatments have limitations. Anterograde and
retrograde anatomical tracings have been used to demonstrate direct (monosynaptic) anatomical connection
between the OFC and the descending inhibitory pain nodes at the midbrain periaqueductal gray matter (PAG).
Transition to CP is marked by weakened modulation of the PAG-descending inhibition. Evon Medics, a small
business specializing in olfactory neurotherapeutics, developed an innovative chemosensory-based
orbitofrontal cortex (OFC) stimulation device, called CBOT-P, for home use, to increase OFC plasticity and
effect OFC-induced regulation of pain and negative affect. We now plan to refine this product for broad pain
conditions and quickly make it available to the population. OFC is the part of the prefrontal cortex that plays
key roles in multisensory integration, affect regulation, and decision-making. The lateral OFC, which is
consistently activated by pain, is connected to other cortical brain regions that process pain; and the medial
OFC, which networks with medial temporal affect networks, is engaged by mindfulness therapy for pain and
plays important role in positive affect and drive. Unfortunately, CP and opioid analgesics are associated with
OFC shrinkage, which amplifies pain through increased negative affect (NA) and cognitive impairment. The
success of CBOT-P in acute relief of NA and pain in our pilot studies is not surprising because single-pulsed
electrical stimulations with OFC-placed electrodes acutely relieved NA in humans in invasive deep brain
stimulation, and experimentally induced stimulation of the OFC in animal models and humans activates the
PAG to reduce pain sensitization. The CBOT-P uses Evon’s proprietary regimen of 10 odorant phytochemicals
to stimulate the secondary olfactory cortex (i.e. the OFC) repetitively, with established micro-controller-
regulated stimulation parameter settings that maintain persistent activation of the OFC and medial temporal
regions, without habituation; paired with digitally-administered olfactory psychophysical training tasks that
activate same regions, for synergistic effect on long-term neuroplasticity changes that prevents CP-induced
shrinkage. As a second mechanism of action, the olfactory stimulants were fortified with proprietary
components, such as beta-caryophyllene (BCP), a selective endocannabinoid-2 receptor agonist, which has
strong anti-inflammatory and antinociceptive effects, and scalable for acute positive affect.
In the Phase I of this Fast-Track SBIR application, we will (a) configure CBOT-P regimen and
stimulation parameters for faster onset of mood elevating and analgesic effects, focusing on Chronic Low Back
Pain populations and (b) establish its neural mechanism of action through target-engagement studies of OFC
activity and functional connectivity with other pain regulating regions at baseline. In Phase II, we will perform a
powered randomized trial of the refined CBOT-P from Phase I, compared to sham CBOT in CLBP, to
determine its short- and long-term effectiveness on Pain, Affect, Cognition and cortical brain Structure (PACS),
long-term safety, and indications. We will also collect user experiences to help refine a final marketable CBOT
product, enter the FDA breakthrough designation program for pain that would lead to Medicare/Medicaid
reimbursement, engage a wider network of pain stakeholders, and establish marketing for commercial
success. Project success will be enhanced through strong collaborations between Evon Medics, Johns
Hopkins (JHU) Pain Center, Howard University investigators, community pain providers and collaborating
manufacturers. To the best of our knowledge this will be the first home-based combinatorial digital-
chemosensory neuromodulatory product for stimulation of deep brain regions for CP management.
Terms: <Acute><Acute Pain><Affect><Affective><Agonist><American><Analgesic Agents><Analgesic Drugs><Analgesic Preparation><Analgesics><Anatomic Sites><Anatomic structures><Anatomy><Animal Model><Animal Models and Related Studies><Anodynes><Anti-Inflammatories><Anti-Inflammatory Agents><Anti-inflammatory><Anticonvulsant Agent><Anticonvulsant Drugs><Anticonvulsants><Anticonvulsive Agents><Anticonvulsive Drugs><Antinociceptive Agents><Antinociceptive Drugs><Anxiety><Behavior Conditioning Therapy><Behavior Modification><Behavior Therapy><Behavior Treatment><Behavioral Conditioning Therapy><Behavioral Modification><Behavioral Therapy><Behavioral Treatment><Beta-caryophyllene><Brain><Brain Nervous System><Brain region><Businesses><CNS plasticity><Cessation of life><Chemical Dependence><Chronic low back pain><Clinical><Cognition><Cognitive><Cognitive Disturbance><Cognitive Impairment><Cognitive decline><Cognitive function abnormal><Collaborations><Communities><Conditioning Therapy><Data><Death><Decision Making><Deep Brain Stimulation><Development><Devices><Disturbance in cognition><Dose><Drug Addiction><Drug Dependence><Drug Dependency><E-stim><Effectiveness><Electric Stimulation><Electrodes><Emotions><Encephalon><Endocannabinoids><Endogenous Cannabinoids><Enrollment><Evaluation><Exercise><Feasibility Studies><Financial Hardship><Fortification><Funding><Home><Human><Impaired cognition><Intervention><Intervention Strategies><Intractable Pain><Investigators><Lateral><Long-Term Effects><Longterm Effects><Manufacturer><Marketing><Measures><Medial><Medicare/Medicaid><Mental Depression><Mesencephalic Central Gray><Mesencephalon><Mid-brain><Midbrain><Midbrain Central Gray><Midbrain structure><Mindfulness Approach><Mindfulness Therapy><Mindfulness Training><Mindfulness Treatment><Mindfulness-based Approach><Mindfulness-based Therapy><Mindfulness-based Training><Mindfulness-based Treatment><Modern Man><Moods><Motivation><NIDA><Narcotic Analgesics><National Institute of Drug Abuse><National Institute on Drug Abuse><Neuronal Plasticity><Neurosciences><Olfactory Cortex><Operative Procedures><Operative Surgical Procedures><Opioid Analgesics><Outcome><Overdose><Pain><Pain Centers><Pain Clinics><Pain Control><Pain Relief Units><Pain Therapy><Pain intensity><Pain management><Painful><Pathologic><Pathway interactions><Patients><Periaqueductal Gray><Persons><Phase><Physiologic pulse><Phytochemical><Pilot Projects><Play><Population><Prefrontal Cortex><Prevention><Process><Provider><Psychophysics><Pulse><Randomization trial><Randomized><Randomized, Controlled Trials><Receptor Protein><Refractory Pain><Regimen><Regulation><Research><Research Personnel><Researchers><Rewards><Role><SBIR><Safety><Sensory><Severities><Site><Small Business Innovation Research><Small Business Innovation Research Grant><Stimulant><Stimulus><Structure><Subgroup><Surgical><Surgical Interventions><Surgical Procedure><Technology><Testing><Time><Training><Universities><acute to chronic pain transition><anatomical tracing><annulus of the aqueduct><anti-depressant agent><anti-depressant drugs><anti-depressants><anti-depressive agents><antinociception><antinociceptive><attenuation><behavior intervention><behavioral intervention><care as usual><central nervous system plasticity><central pain><chronic back pain><chronic pain><chronic pain condition><chronic pain control><chronic pain disorder><chronic pain intervention><chronic pain management><chronic pain patient><chronic pain therapy><chronic pain transition><chronic pain treatment><chronic painful condition><co-morbid><co-morbidity><cognitive dysfunction><cognitive function><cognitive loss><combinatorial><comorbidity><computerized><cortical pain><cost effective><depression><developmental><digital><disability><drug relapse><effective intervention><effective therapy><effective treatment><effectiveness/implementation hybrid study><effectiveness/implementation study><efficacy study><electrostimulation><emotion 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use><opiate use disorder><opioid analgesia><opioid anesthetic><opioid consumption><opioid drug use><opioid intake><opioid misuse><opioid pain medication><opioid pain reliever><opioid painkiller><opioid use><opioid use disorder><pain chronification><pain killer><pain medication><pain patient><pain processing><pain reduction><pain relief><pain reliever><pain sensitivity><pain treatment><painkiller><pathway><patient centered><patient oriented><patient with chronic pain><periaqueductal gray matter><pilot study><plant compound><plant derived compound><prevent><preventing><programs><psychophysical><randomisation><randomization><randomized control trial><randomized trial><randomly assigned><receptor><reduce pain><relieve pain><response><seizure drug><seizure medication><sensory integration><side effect><social role><stimulus interval><substantia grisea><success><surgery><transition to chronic pain><treat chronic pain><treatment as usual><trend><user-friendly><usual care><β-caryophyllene>