Clinical trial NCT05452694: OpalGenix- Personalized Postoperative Pain Management Following Lumbar Spinal Fusion and Decompression Surgery in Adults
Official title: Pharmacogenetics and Pharmacokinetics of Oxycodone to Personalize Postoperative Pain Management Following Lumbar Spinal Fusion and Decompression Surgery in Adults
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Lumbar Spine Stenosis
Lumbar Spine Degeneration
Keywords: Pain Management
Lumbar Spine Stenosis
Degenerative Lumbar Spine
Opioid Use
Lead sponsor: OpalGenix, Inc
Sponsor class: INDUSTRY
First posted: 2022-07-11
Enrollment: 235
Sex: ALL
Minimum age (years): 18
Maximum age (years): 99
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Study population will be adults undergoing lumbar spine surgeries that fit the inclusion criteria. Children will not be included as they are not seen at the specific site institution. Given the nature of the surgical procedure, pregnant women and women that may be pregnant will also not be included in this study population.

Brief summary: The proposed research is an important extension of an ongoing perioperative personalized analgesia and intravenous opioid pharmacogenetic research. This research focuses on two of the most commonly used oral opioid analgesics, oxycodone, and methadone, in adults following lumbar spinal fusion and decompression surgery. Genetic signature and combinatorial pharmacogenetic approaches perform better than single-gene associations. This innovative translational research will for the first time evaluate simultaneously the effects of multiple genes and interactions on oxycodone and methadone's pharmacokinetics and optimal clinical dosing and on its safety and efficacy in the highly vulnerable pediatric population. This research's multigenetic signature findings can be easily extrapolated to adults undergoing surgery or using oxycodone and/or methadone for chronic and cancer pain and in identifying opioid abusers at risk of severe respiratory depression and death.

When methadone is given in addition to oxycodone for inpatient pectus excavatum repair and idiopathic scoliosis spinal fusions according to new departmental protocols, methadone pharmacokinetics and pharmacodynamics will also be evaluated.

Detailed description: Multilevel lumbar spinal fusion and decompression surgeries (LSS) are common and extremely painful inpatient procedures associated with severe post-surgical pain, high incidence of CPSP, persistent and excessive opioid use, unsafe opioid prescribing and development of opioid use disorder (OUD), along with costly immediate postoperative opioid adverse events (AEs) and long hospital stays. Opioids are still widely used to manage acute surgical pain and remain a core component of multi-modal analgesic and enhanced recovery after surgery protocols (ERAS) for painful surgeries. About half of LSS patients 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) that frequently delay recovery, require additional treatment or monitoring, increase cost of care, and prolong hospital stay. Long-term risks include opioid dependence, opioid-use disorder (OUD), and the consequent personal, financial and societal fall-out from opioid addiction.

While in the hospital, LSS patients report suboptimal surgical pain (and AEs) with short-acting opioids such as morphine, hydromorphone, and fentanyl. Post-discharge, despite receiving additional potent prescribed opioids such as oxycodone for \>1-2 weeks at home, 20-50% of patients develop CPSP, largely due to suboptimal immediate surgical pain relief (the single greatest risk factor for CPSP). Patients who develop CPSP have high life-long risks for opioid use and misuse, contributing to the ongoing opioid epidemic and lost productive life. Poor surgical pain relief and opioid- AEs therefore result in negative consequences for patients, families, providers, and society, and constitute significant socio-economic burden. Thus, there is an urgent and unmet clinical need for a reliable and proactive tool to reduce opioid use and opioid-related AEs, enhance pain relief and prevent CPSP following painful surgeries.

CPSP is common following LSS: Effective and aggressive acute surgical pain management is critical to lower risks of developing CPSP. In a large prospective study assessing pain outcomes from 21 hospitals in 11 European countries (PAIN OUT cohort)120, 11.8% of patients reported moderate to severe CPSP at 12 months. The three risk factors for CPSP at 12 months, chronic preoperative pain, type of surgery and percentage of time in severe acute surgical pain, are very common in LSS patients. Importantly, orthopedic surgery is associated with 3-fold higher risk for CPSP compared with all other procedures. 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). LSS is often associated with severe acute post-surgical pain, a high incidence of CPSP, excessive and persistent opioid use increasing cost of care significantly with high worker compensation costs with lost productivity. Thus, there is a clear need for more effective and safer pain management following LSS to prevent CPSP, risks of lost productivity, excessive opioid use, misuse, dependence and OUD.

High inter-individual variations in response to opioids can be explained by genetics and clinical risk factors, 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 pain control and adverse outcomes with different opioids. Through genotype-based opioid selection, precision dosing and outpatient tailored opioid prescribing improve outcomes, there are many translational barriers. An important example is the use of CYP2D6 phenotyping to guide dosing or use of codeine, tramadol, hydrocodone, and oxycodone for improved safety and efficacy.

OpalGenix intends to revolutionize perioperative opioid and pain management with proactive and personalized risk prediction algorithms with \>70% accuracy in predicting opioid AEs for precision pain and opioid management. GPS-Opioid will be a 510(k) cleared medical device that will enable preoperative genotyping of important and patented polygenetic markers shown to impact clinically and economically meaningful perioperative opioid and pain outcomes. The polygenetic markers predict opioid AEs better than single-gene associations: each gene, including CYP2D6, explains only 5-10% of clinical response variations while polygenetic models have \>70% predictive accuracy as they combine important pharmacodynamics genes with well-known but less important genes involved in opioid metabolism such as CYP2D6. In addition, polygenetic models account for the synergistic effects of multiple risk alleles. Uniquely, GPS-Opioid also includes patented clinical risk factors with polygenetic signatures using a proprietary algorithm to identify patients at risk for experiencing uncontrolled severe pain, opioid-related AEs including RD and PONV, prolonged hospital stay, CPSP, opioid dependence and potential for developing OUD. Integration of GPS-Opioid in EHR, at the point-of-care, will enable perioperative clinicians with critical information they need to develop a personalized ERAS pain management plan prior to surgery to proactively minimize/eliminate costly opioid related adverse events, enhance surgical pain relief and avoid CPSP

Eligibility criteria: Inclusion Criteria:

* \>18 years of age
* American Society of Anesthesiologists (ASA) Physical Status 1, 2, or 3
* Undergoing lumbar spine surgeries (lumbar spine decompression, multilevel posterior spine fusion, internal fixation or a combination) for degenerative lumbar spine and lumbar spinal stenosis and requiring opioids for perioperative pain management

Exclusion Criteria:

* Children (\<18 years of age)
* Pregnant women
* American Society of Anesthesiologists (ASA) Physical Status 4 or above
* Non-English speaking
* Outpatient surgery
* Concomitant additional surgical procedures
* Significant liver or kidney dysfunction
* Significant cardiorespiratory compromise
* Patients with polysubstance use (e.g., cocaine, marijuana, amphetamine, etc.)

Primary outcomes:
measure: Opioid-related Post-operative nausea and vomiting (PONV)
timeFrame: Post-operative up to 12 months
measure: Opioid-related sedation
timeFrame: Post-operative up to 12 months
measure: Opioid-related respiratory depression (RD)
timeFrame: Post-operative up to 12 months
Secondary outcomes:
measure: Opioid use
timeFrame: Pre-operative to post-operative up to 12-months
measure: Post-operative Pain Scores
timeFrame: Pre-operative to post-operative up to 12-months
measure: Length of Hospital Stay
timeFrame: Post-operative day 1 up to 1-month
measure: Chronic Post-surgical Pain (CPSP)
timeFrame: Post-operative up to 12 months
measure: Length of Prescribed Opioid Usage
timeFrame: Post-operative up to 12-months
measure: Opioid Dependence (OD)
timeFrame: Post-operative up to 12 months
measure: Opioid Use Disorder (OUD) Risk
timeFrame: Post-operative at 3-months
measure: Differences in fNIRS signals
timeFrame: Preoperative
measure: QST Battery Responses
timeFrame: Preoperative
measure: Pain intensity scores after stair climbing task
timeFrame: Preoperative
measure: Pain intensity scores after walking test
timeFrame: Preoperative
measure: Duration of stair climbing task
timeFrame: Preoperative
measure: Distance walked during 6-minute walking task
timeFrame: Preoperative
Other outcomes:
Locations:
city: Pittsburgh
country: United States
facility: UPMC Montefiore Hospital
state: Pennsylvania
city: Pittsburgh
country: United States
facility: UPMC Presbyterian Hospital
state: Pennsylvania
city: Pittsburgh
country: United States
facility: UPMC Pain Medicine at Centre Commons
state: Pennsylvania
Study officials:
affiliation: University of Pittsburgh
name: Kathirvel Subramaniam, MD, MPH
role: PRINCIPAL_INVESTIGATOR
References: