Minimizing the Guessing Game in Pain Management

A New Study Brings Pharmacogenetics to Postoperative Care

September 5, 2023 - by Jennie Ellison

Patients preparing to undergo surgery face many unknowns. Will the surgery improve their quality of life? How long will they take to recover? Many are concerned about the pain and discomfort surrounding the surgery. What they may not be considering is how their body will respond to pain medication(s) prescribed during and after surgery. 

The surgical co-management (SCM) team in the division of hospital medicine is a group of internal medicine physicians who optimize care of patients admitted to the neurosurgery, orthopaedic surgery, and ear, nose, and throat (ENT) divisions. SCM works collaboratively with surgical teams to minimize the risk of medical complications in the perioperative period (i.e., the time leading up to, during, and following surgery). 

“Effective and individualized pain management in the perioperative period is crucial in reducing the risk of many medical complications, such as respiratory depression, delirium, or ileus,” says Nidhi Rohatgi, MD, MS, clinical professor of hospital medicine and section chief for SCM.

Doctors base pain medication plans on current medical guidelines, which account for factors such as patient age, co-morbidities, and the extent/duration of the surgery. Yet outside of these factors, there is “significant variability in postoperative opioid requirements among patients,” says Rohatgi. This variability can be due, in large part, to an individual’s genome. 

Drug metabolism is a highly specific scenario: select gene groups code for particular enzymes, which metabolize medications. A variant or mutation in an individual gene group will cause distinct levels of an enzyme’s activity, directly impacting the drug metabolic process. 

In an effort to reduce postoperative medical complications related to pain management, Rohatgi launched a pilot study for spine patients in neurosurgery that combines the current pain management protocols with a patient’s unique drug metabolism. Certaingene variations cause some patients to process medications at a faster rate than average. Other patients do not metabolize certain categories of medications quickly or at all, so the usual dosages or categories will not work for them. This genetic variation and its impacts have not been included as a part of current best practices for prescribing pain medications after surgery.

Doctors Veeravagu, Rohatgi, and Palaniappan (from left to right)

Stanford’s first pharmacogenetics inpatient study

Pharmacogenetics is the study of how patients will respond to medication based on their individual genome. Rohatgi is leading a feasibility study that incorporates pharmacogenetics into the inpatient process for complex spinal surgery patients. Pharmacogenetics testing shows variations in expression of various genes in an individual patient, such as CYP2D6, which codes for enzymes necessary for pain medication metabolism. This testing can also help optimize other medications the patient has been prescribed if there are pharmacogenetics guidelines for those medications. The results can provide answers to two big questions: what? (type(s) of medication are best) and how much? (appropriate dosage).

According to Rohatgi, the catalyst for the pharmacogenetics initiative in neurosurgery spine patients was the challenges faced in postoperative pain management. The neurosurgery team and SCM have co-created a pain management order set for spine surgery patients to avoid side effects and manage pain. This order set has worked well for many patients. However, there are three subgroups of patients that would benefit from more personalized pain management: patients who experience very high pain levels with the usual medication dosages, patients who experience very high pain levels despite very high medication dosages, and patients who experience side effects from pain medications at usual or very low dosages.

The risks with pain medications can be extremely high: over-sedation, breathing complications, delirium, ileus, and urinary retention can all result from pain medications. “And this just cascades into poor mobility, deconditioning, pneumonia and other infections, blood clots, falls, transfers to the intensive care unit (ICU), longer stays in the hospital, higher chance of going to a rehabilitation facility instead of home after the surgery, and breakdown in trust between the patient/family and the inpatient team,” says Rohatgi.

“When the pain is intense, it is hard for anyone to comprehend why they are not being given more pain medications. We are worried about side effects with pain medications and the patient/family is understandably worried about pain,” Rohatgi says. “These patients may get labeled as ‘drug seeking’ or ‘challenging,’” she adds.

However, with pharmacogenetics-guided medication plans, she can know if a patient is a rapid metabolizer and will need higher dosages of certain pain medications. Alternatively, for poor metabolizers, even the highest dose of certain pain medications is likely going to be ineffective, and these patients can be switched to a different medication.

Pharmacogenetics gives physicians “additional objective data to minimize this guessing game — to give or not to give more pain medications, which ones will work better for that particular patient, and which patients are at higher risk of getting side effects.”

This testing can also help optimize other medications the patient has been prescribed if there are pharmacogenetics guidelines for those medications. The results can provide answers to two big questions: what? (type(s) of medication are best) and how much? (appropriate dosage).

While pharmacogenetics has been used in Stanford’s primary care setting in the Humanwide Project, this research is the first pharmacogenetics study in the inpatient postoperative setting at Stanford. Rohatgi is working alongside Anand Veeravagu, MD, associate professor of neurosurgery and orthopedic surgery, and Latha Palaniappan, MD, MS, professor of cardiovascular medicine, scientific director of precision genomics and pharmacogenomics in primary care, and faculty co-director of the Stanford Pharmacogenomics Consult Service.

Veeravagu’s spinal surgery patients are given the opportunity to participate in pharmacogenetics testing. Patients typically have a four- to six-week wait until surgery. During that time, they are sent an in-home buccal swab kit for genetic testing, which they complete and mail to an off-site testing location. Rohatgi and Palaniappan, the neurosurgery team, and Stanford pharmacists receive the results two to three weeks later, at which time they analyze the results.

Once the patient gets admitted to the hospital, Rohatgi and the rest of the SCM team incorporate the results of the pharmacogenetics testing into the patient’s postoperative medication management plan. Without pharmacogenetics testing, “it was your best clinical judgment,” says Rohatgi. “The thing is, we never included pharmacogenomics in our actual practice despite the evidence.”

Patient enrollment in the pharmacogenomics study for spine patients started in February 2023 and is ongoing. Rohatgi’s team will analyze several outcomes: 1) prescribed medication changes due to pharmacogenetics testing for the inpatient setting and for long-term home medications; 2) medical complications; and 3) patient-reported pain scores. So far, there have been no instances of over-sedation or delirium related to pain medications for these patients after complex spine surgeries.

The Surgical Co-Management (SCM) Team

The future for pharmacogenetics-guided medicine

The challenges to pharmacogenetics-guided treatment are the usual suspects for most innovative technologies: time, money, and data coordination. Stanford does not currently have on-site testing, which could allow physicians to order tests and receive the results more easily and quickly. In a few cases, the study team has not received a patient’s pharmacogenetics results before their surgery date. 

“I think the key roadblock for use of pharmacogenetics in the hospital setting is the turnaround time,” Rohatgi says. And while testing is covered by many payors and none of the patients have experienced high out-of-pocket testing costs, the pilot study does not cover pharmacogenetics testing costs, so there could be cost barriers going forward for some patients. 

There is also a need for better data management software, which would allow pharmacogenetics to be integrated into a patient's electronic medical record. This is especially important when it comes to incorporating genetic testing results with a patient’s current medications, as certain drugs can change a normal metabolizer into a poor metabolizer. 

A patient’s medical condition can change quickly in the hospital setting, as new medications can be added in a span of minutes. “If the pharmacogenetics profile is eventually incorporated into our electronic medical record and can provide real-time decision support, it would be a huge step forward for our patients. There is often no time to review the pharmacogenetics guidelines for every medication for every patient or wait for the pharmacy to review the medications. If the data is available at our fingertips, it is more likely to be used,” says Rohatgi. 

Pharmacogenetics is being used across medical specialties and patient settings outside of Stanford. Other studies have analyzed how pharmacogenetics can assist in guiding the administration of antiplatelet drugs for cardiovascular patients and immune-suppressing drugs for transplant recipients, as well as a multi-center pharmacogenetics-guided opioid prescription study for surgical patients currently underway.

These studies represent the early days of pharmacogenetics research, which Rohatgi says has not had “its prime time yet.” She has been approached by other Stanford physicians about the feasibility of using pharmacogenetics testing in their clinical settings and hopes this pilot study is just the beginning. She also is keeping an eye on Stanford’s Catalyst Program, which has recently funded a project to create a point-of-care pharmacogenomics solution.

Rohatgi shares, “I hope we can make Stanford Medicine the preeminent hub for pharmacogenetics clinical practice and research in the future, with a team science approach. The mission of our surgical co-management team is to collaborate, connect medicine and surgery, innovate, and evolve to provide the best possible care to our surgical patients.”

“This is a huge step forward in providing personalized precision medicine to our patients,” Rohatgi concludes. “Why wouldn’t we want that?”

“The mission of our surgical co-management team is to collaborate, connect medicine and surgery, innovate, and evolve to provide the best possible care to our surgical patients.” - Nidhi Rohatgi, MD, MS