Risks associated with post-TS pain and opioids. Opioids are still widely used to manage
acute surgical pain and remain a core component of enhanced recovery after surgery
protocols (ERAS) for painful TS. With current approaches that incorporate ERAS protocols,
half of TS patients still suffer from uncontrolled severe surgical pain and significant
adverse opioid effects due to opioids' narrow therapeutic indices and unpredictable
inter-individual variations in pain perception and opioid responses. Risks associated
with perioperative opioid use include immediate risks (life-threatening respiratory
depression (RD), excessive sedation, postoperative nausea and vomiting (PONV), urinary
retention, constipation, ileus and itching) frequently delay recovery, require additional
treatment or monitoring, increase cost of care, and prolong hospital stay. Long-term
risks include CPSP, opioid dependence, OUD, and the consequent personal, financial and
societal burden of opioid epidemic. Post-TS CPSP: A 10% increase in the percentage of
time in severe pain on the first postoperative day was associated with a 30% increase in
the incidence of CPSP at 12 months (N=889), post-thoracotomy pain and TS are associated
with the highest risk for CPSP compared with all other procedures. Effective and
aggressive acute surgical pain management is critical to lower risks of developing CPSP.
Opioids are still an important part of managing surgical pain following TS. Postoperative
pain following TS is often excruciating and challenging to treat as it provokes
nociceptive, neuropathic and spasmodic muscle pain. Current standardized ERAS multimodal
analgesic approaches include non-opioid analgesics to minimize opioids during and after
surgery. While ERAS protocols have reduced immediate perioperative opioid use, they
follow a "one size fits all" trial-and-error reactive standardized practice, and at risk
patients continue to experience uncontrolled pain, CPSP, costly opioid AEs and persistent
opioid use.
High inter-individual variations in response to opioids can be explained by genetics, yet
translational barriers prevent widespread adoption of genotype-guided care: Our many
studies on genetic predictors of postoperative pain and opioid-related AEs, and published
literature from other researchers demonstrate that genetic and clinical factors are
associated with inter-individual variations in surgical pain and opioid AEs. Personalized
care based on validated and actionable polygenic and modifiable clinical risk factors
(e.g., anxiety, depression, catastrophizing, poorly controlled acute postoperative pain)
can transform and enhance post-TS pain and opioid management. Thus, there is an urgent
and unmet need for a highly reliable preoperative tool to predict and prevent severe
pain, CPSP and opioid-related AEs.
Inadequate acute postoperative pain management predisposes patients to the development of
CPSP and contributes to opioid dependence (OD), opioid misuse, and loss of productivity
in society. Opioids are continued after discharge in 76.4% of patients, with a median
discharge prescription of 150 mg oral morphine equivalents. More than a third of thoracic
surgical patients develop CPSP at 3 months after surgery and poor postoperative pain
control predicts both incidence and severity of CPSP. Patients who develop CPSP have a
high life-long risk of opioid use and misuse contributing to addiction, and overdose
deaths.
Poorly controlled surgical pain, excessive opioid use, and CPSP lead to postoperative
neurocognitive disorders including delirium, postoperative cognitive dysfunction (POCD),
and dementia. Delirium is detected during hospitalization and neurocognitive decline
lasting longer (>30 days) is described as POCD. Untreated pain and excessive
perioperative opioids increase the risk of delirium and POCD in elderly individuals. A
population-level Health and Retirement study of 10,065 patients >62 years old showed CPSP
is common and was associated with accelerated memory decline and increased probability of
dementia.
Both poorly controlled pain and excess opioid use predispose elderly surgical patients to
postoperative delirium, POCD and dementia. New persistent opioid use is a significant
public health problem in elderly surgical patients.
The OpalGenix Solution: GPS-Analgesics. As a Global Positioning System (GPS) helps chart
a course in unknown/unfamiliar terrain, GPS-Analgesics TM (Genotype-guided Physician
Support for Analgesics Use) is designed to support physicians to proactively identify
patients genetically predisposed to high risks for severe surgical pain, CPSP and opioid
AEs. In this Phase I proposal, OpalGenix will build on our prior studies to develop and
validate GPS-Analgesics in TS patients. We have extensively and prospectively studied
~2000 patients undergoing painful surgeries and demonstrated that the high individual
variation observed in responses to surgical pain and opioids can be explained by a
combination of polygenetic and clinical factors. Specifically, inter-individual surgical
pain, and opioid variability were partly and independently explained by specific
polymorphisms of the genes ABCB123, OPRM143, CYP2B6110, ABCC351,52, FAAH22, COMT53 and
OCT151. However, these single-gene associations independently explain only a small
(5-15%) portion of inter-individual variability in pain- and opioid responses.
GPS-Analgesics is a novel combinatorial pharmacogenetic polygenetic tool with high
accuracy (>90%) integrating clinical risk factors to better explain the cumulative
effects (>90%) of both polygenetic (50-60%) and clinical (40-50%) risk factors on
surgical pain and analgesics responses. OpalGenix's novel prototype predictive software
algorithm based on patented polygenic risks already has >80% predictivity. At the end of
this Phase I, GPS-Analgesics will provide >90% high accuracy, evidence-based,
personalized surgical pain while avoiding opioid-related AEs.
