Findings in knee replacement patients show cannabis-like molecules may influence pain levels and recovery
The Takeaway:
A CU Anschutz-led study suggests acetaminophen may relieve pain by interacting with the body's endocannabinoid system, which regulates pain and inflammation. In knee replacement patients, changes in cannabis-like molecules were linked to both acetaminophen use and reported pain levels. These findings could inform more targeted pain therapies in the future.
Despite acetaminophen's popularity as a pain reliever, we don't fully understand how it works.
In 2008, Nathan Clendenen, MD, assistant professor of anesthesiology at the CU Anschutz School of Medicine, saw a study in mice suggesting that acetaminophen works within the endocannabinoid system - a natural system found in everyone that helps regulate pain, inflammation and other essential functions.
Clendenen wondered if it was true in people, too. It led him to study patients undergoing knee replacement surgery, where he found that in people with arthritis pain, the levels of the body's own cannabis-like molecules shifted after surgery and were associated with acetaminophen use. The endocannabinoid changes were also linked to how much pain patients reported.
"The study gave us clues to how acetaminophen might be working," Clendenen said, adding that while the finding is interesting, it's not enough to change clinical practice. But it has identified patterns that may offer potential for future therapeutic interventions.
Definitions:
Endocannabinoid system: A natural system in the body that helps regulate pain, mood, inflammation and other functions through signaling molecules and receptors.
Anandamide: A naturally-occurring endocannabinoid involved in pain regulation and mood.
2-arachidonoylglycerol (2-AG): Another key endocannabinoid that helps regulate inflammation and pain signaling.
Cross-tolerance: When exposure to one substance reduces the effectiveness of another.
What is the endocannabinoid system, and why does it matter?
Complex and still not fully understood, the endocannabinoid system was identified by researchers in the 1980s who were trying to understand why the psychoactive compound in cannabis - tetrahydrocannabinol (THC) - produces a high. They found that THC binds to certain proteins, or receptors, throughout the brain and nervous system.
This led to the discovery that the body itself naturally produces cannabis-like molecules. These endocannabinoids play a key role in regulating everything from mood and memory to appetite and sleep.
Clendenen's study shines a light on the endocannabinoid system and the experience of pain.
Isolating pain experiences and acetaminophen use in knee surgery
"People are so different, so studying how acetaminophen and the endocannabinoid system work in relation to pain is tricky," Clendenen said.
He looked at patients undergoing total knee replacement surgery at Mayo Clinic in Jacksonville, Fla. There, it's standard for all patients to receive intravenous (IV) acetaminophen.
The study team collected cerebrospinal fluid and blood samples from 40 adults at three points: before surgery, shortly after patients received IV acetaminophen and again 24 hours after the operation. The researchers tracked the levels of the two primary endocannabinoids - anandamide and 2-arachidonoylglycerol - to see how these cannabis-like molecules changed.
They also tracked patients' pain scores before, during and after surgery for up to a year.
"It's easy to study people for a week, but it's a lot harder once they leave the hospital, especially if they don't have problems," he said. But overall, the researchers were able to get responses from about 70% of the patients over the year.
Clendenen was interested in the experiences of patients who had postsurgical pain, looking for patterns that might explain what was different about their experiences. They found that patients with osteoarthritis had higher levels of anandamide and related compounds (N-acylethanolamines) compared to people without the condition.
Patients reporting more severe pain showed a different pattern: lower levels of anandamide before and after surgery. They also had higher levels of another compound, 2-arachidonoylglycerol, but only before surgery.
The findings suggest that chronic pain, surgery and acetaminophen may all interact with the body's endocannabinoid system to help regulate pain and inflammation. This could explain why patients experience pain differently.
"So now a question emerges - if you present to surgery with low levels of anandamide, could we bump this up or activate a pathway that could allow the patient to have better pain outcomes?"
"One idea is that people who use cannabis a lot may be wearing out their endocannabinoid receptors, so when you need them to work for surgery, they aren't as effective." - Nathan Clendenen, MD
How does using cannabis impact pain?
As an anesthesiologist working in one of the first states to legalize cannabis use, Clendenen has long been interested in how using the substance impacts patients. Anecdotally, Clendenen shared that there is cross-tolerance between cannabis and the anesthetic propofol, meaning propofol can be less effective in people who use cannabis. So far, studies have consistently shown they are associated but the two drugs aren't known to act on the same biological pathways, suggesting unknown mechanisms at play.
Linking acetaminophen and the endocannabinoid system has helped inform a new multidisciplinary CU Anschutz study funded by the National Institute of Neurological Disorders and Strokes. Over five years, the team, including Clendenen and other researchers in the Department of Anesthesiology, will study how cannabis use affects pain outcomes after knee replacement surgery.
Using both animal models and clinical trials, they will examine how the endocannabinoid system shapes how inflammatory pain in osteoarthritis develops, persists and resolves in both cannabis users and non-users.
"We're taking the next step and asking whether people who use cannabis do better or worse when it comes to pain," Clendenen said. "One idea is that people who use cannabis a lot may be wearing out their endocannabinoid receptors, so when you need them to work for surgery, they aren't as effective."
Tapping the potential for more targeted pain relief
Clendenen points to acetaminophen's origins as an example of how our understanding of substances evolves. In the late 1800s, scientists studying chemicals tied to aniline dyes - used to make indigo for blue jeans - led to the development of early pain relievers. Decades later, they realized those drugs worked because the body converted them into acetaminophen, a byproduct formed as the compounds are broken down.
The knee replacement study findings suggest a similar potential for tapping into the endocannabinoid system. Rather than acting through a single pathway, acetaminophen appears to influence a cascade of cannabis-like molecules tied to sleep, anxiety and different types of pain.
"There are these distinct, almost like fingerprints of different markers that we could see," he said.
That insight points to new possibilities. Just as acetaminophen emerged by isolating a beneficial downstream compound, researchers may be able to trace how cannabis-related molecules are processed in the body and target the ones driving specific effects.
"Maybe you can go further downstream to isolate compounds that can make a better sleep aid without the munchies and all the other problems."
The upcoming trials are where Clendenen's work starts to come together to make an impact.
"We've got an interesting scientific question, people who need help and a clear knowledge gap," he said. "We designed this study to take a step closer to helping people identify patterns, and it's a first step toward helping a massive number of people by eventually influencing clinical practice."
Key findings:
Acetaminophen may relieve pain by interacting with the body's natural endocannabinoid system, which regulates pain and inflammation.
Changes in cannabis-like molecules were linked to both acetaminophen use and how much pain patients reported after knee surgery.
Patients with more severe pain had lower levels of the endocannabinoid anandamide before and after surgery.
People with osteoarthritis showed higher levels of certain endocannabinoids compared to those without the condition.
Findings suggest targeting the endocannabinoid system could lead to more precise and personalized pain treatments.
