Opioids and the Brain: What We Knew, What We Know Now, and What the Future Could Look Like

At the 2018 IASP World Congress on Pain, Jane Ballantyne advocated for the use of non-drug therapies that engage the body’s own opioid system to manage chronic pain. Image credit: sergio77/123RF Stock Photo.

Editor’s Note: At the 2018 World Congress on Pain in Boston, the biennial meeting of the International Association for the Study of Pain, researchers from around the world gathered to discuss the latest pain research. Twelve young scientists attending the World Congress were selected to provide first-hand reporting from the event, as part of a science communications training program provided by the Pain Research Forum, RELIEF’s parent site. Here, Francie Moehring, PhD, who is doing post-PhD pain research at the Medical College of Wisconsin, Milwaukee, US, reports on a plenary lecture delivered at the meeting by Jane Ballantyne, MD, a professor of anesthesiology and pain medicine at the University of Washington, Seattle, US. 

During her plenary talk at the 2018 International Association for the Study of Pain (IASP) World Congress on Pain, Jane Ballantyne discussed how opioids affect the brain, what the pain field has learned over the years about the use of these drugs, and the path she thinks doctors should now follow to improve the treatment of chronic pain and decrease opioid use, particularly in the US.

Ballantyne, a pain physician, was an early proponent of limiting opioid prescriptions for people with chronic pain. The message of her talk was that long-term opioid use can have severe consequences that disproportionally affect vulnerable individuals with pre-existing mental health and addiction problems. She urged caution about the use of opioids over extended periods of time, and strongly encouraged exploring non-drug approaches that engage the body’s own built-in opioid system.

Natural opioids
“People have used opiates for thousands of years,” Ballantyne said at the beginning of her talk. But it was only much more recently, in the 1960s, when the first knowledge of how opioids work to ease pain started to emerge.

Ballantyne described how, in the 1960s and 1970s, pharmacologists in the United States who performed research on drug-addicted prisoners at so-called narcotics farms—government-funded prisons, rehabilitation centers and research centers all rolled into one—predicted the existence of the body’s own opioid receptors. These are proteins to which opioids attach, a process that in turn generates a signal inside a cell that ultimately leads to pain relief.

In the early 1970s, researchers identified four different types of opioids receptors in the brain and outside of the brain. As researchers continued to investigate opioids in animal models of pain, they showed that these receptors could be activated by morphine, which eased pain in the models. Researchers then began to search for and find so-called endogenous opioids—natural morphine-like chemicals made by the body and brain.

Despite the discovery of the endogenous opioid system, opioids were still considered as drugs that relieved short-term pain but also caused addiction. Because of the fear of the latter and a belief that opioids were not effective for chronic pain, doctors avoided using opioids for that purpose until the end of the 1980s. That was a time when thinking shifted towards a view that opioid addiction was not a major risk for people with severe chronic pain for whom no other good treatments were available.

Pain relief as a reward
Ballantyne said that the body’s natural reward system and limbic system (which controls emotions, memories and behavioral drives) are inseparable from the pain system. Indeed, the brain perceives pain as punishment, and relief of pain as reward. This may contribute to the addictive nature of opioids—by relieving pain they produce reward.

Many studies have shown that the endogenous opioid system controls this interaction between the pain and reward systems, but why do they interact? It makes sense when considered in the context of survival, where pain relief is essential to an organism’s well being.

In this regard, Ballantyne quoted Frank Porreca, a pain researcher at the University of Arizona, and colleagues who have written that pain should be understood as a behavioral drive that increases the chances of survival: “Pain is a call to action. Like hunger, thirst and desire for sleep, pain is part of the body’s survival systems that collectively are responsible for protecting the organism.”

A multifaceted system
Endogenous opioids do far more than regulate pain and reward. Ballantyne next turned to another interesting function of these natural chemicals, in particular their role in social interactions. It turns out that this particular function of endogenous opioids is also necessary for survival, especially in humans.

Studies in monkeys have shown that endogenous opioids regulate mutual grooming. Meanwhile, other research has demonstrated that giving opioids to socially isolated puppies reduces the vocalizations of distress they normally make when under that circumstance.

In people, the role of endogenous opioids in social behavior is more complex—and even more essential given the absolute necessity for humans to socialize in order to survive. Studies have shown that laughter, singing, and dancing all trigger the production of endogenous opioids, which supports social bonding in larger human groups.

Interestingly, Ballantyne also showed that stress can disrupt the endogenous opioid system. During stressful situations the body makes hormones called corticosteroids and catecholamines, which prepare the body for a “fight-or-flight” response when animals, including humans, feel threatened. Normally, the production of those hormones is balanced by endogenous opioids, which calm the body down and allow for recovery from taxing situations.

However, with repeat or inescapable stress, the endogenous opioid system does not work as well, and more opioids are needed for soothing purposes; the body’s own opioids are no longer enough to balance out the effects of the corticosteroids and catecholamines, resulting in a feeling of being under constant threat. Ballantyne said this malfunctioning system ultimately leads to a state of continuous withdrawal. The situation can also be considered as a state of reward deficiency, she noted.

No reward = chronic pain?
Ballantyne then turned to an interesting question: should chronic pain be considered as a reward problem? To answer this question, it’s important to recognize the difference between acute pain—immediate, short-lasting pain—and chronic pain.

Acute pain serves a protective function, providing a signal to withdraw from harmful situations—removing a hand from a hot stove, for instance—and to rest after an injury. It also serves as a learning tool so a person remembers to avoid that hot stove and other dangerous things. Relief from acute pain is also a rewarding process.

Chronic pain, on the other hand, does not serve any useful purpose; it is not simply acute pain that has not gotten better yet. Ballantyne pointed to previous research suggesting that chronic pain is indeed a disorder of the reward system. That is, in people with chronic pain, because the pain persists, they no longer experience the reward that pain relief provides, and have a weakened capacity to experience pleasure. Ballantyne said this is similar to what happens with opioid abuse, where, over time, the same dose of drug no longer has the same pain-relieving and thus rewarding effects, so a person needs more of the drug.

Interestingly, many of the same brain regions that become engaged during chronic pain are also involved in the effects of both addictive drugs and those that provide pain relief. Changes in nerve cells that occur during chronic pain are also seen during long-term substance abuse.

What are the lessons to learn from the opioid epidemic in the United States?
Ballantyne then shifted gears to discuss the opioid epidemic in the US. She explained that the vast majority of opioid use is actually brief or intermittent by patients undergoing surgery or a short-lived painful event. Most of the time these patients are not the ones who will stay on opioids long term.

Rather, she said, “it is the most vulnerable people who remain on opioids and escalate to high doses,” referring to patients with a history of addiction or mental disorders. High doses are problematic because adverse events, including overdose and death, an inability to come off the drugs, a decreased likelihood of returning to work, higher rates of mental health and substance abuse disorders, and increased chances of the immune system not functioning properly are all more likely to occur when doses are elevated.

“Anecdotal reports suggest that there are many ‘ideal’ patients that do well on opioids, however there are many others that comprise a distressed population with high opioid need and high opioid risk,” Ballantyne said. Data suggest that 75% of those taking opioids for the treatment of chronic pain do not become addicted. However, a subpopulation of these chronic pain patients is especially vulnerable as they have related mental health disorders, which put them at risk of addiction.

That raises a question: is the current opioid epidemic driven not by the dose, but rather by giving opioids to the “wrong” types of patients—those who are most likely to abuse the drugs?

Next, Ballantyne explained that opioid drugs can negatively impact the body’s own endogenous opioid system. Those taking opioids long-term and continuously can also become dependent on the drugs. Ballantyne further said that while many patients take opioids exactly as intended, many are unable to stop taking the drugs even with social and medical support.

With regard to dependence on opioids, this also has social consequences, where patients no longer experience the rewards of social interactions and so become socially isolated. Ballantyne noted that friends of opioid abusers often report that their pals no longer seem the same while on these drugs.

Ballantyne also said that patients who do successfully taper their opioid doses consistently report no longer feeling like “zombies”—and also often report no difference in their pain.

This leads to a conundrum, Ballantyne explained. “People who continue to use opioids are most often the patients for whom nothing else seems to help. Thus opioid use feels life changing.” But these are the same people who are most likely to fare poorly with these drugs over time.

There is also an ethical dilemma, according to Ballantyne: doctors feel comfortable providing medical treatment for physical pain but view non-drug approaches as illegitimate.

The problem, Ballantyne said, is that “physicians prescribe large amounts of dangerous opioids to vulnerable individuals without proper education and control over how these drugs are being taken.” These individuals are more likely to become addicted and suffer from the long-term negative effects of the drugs.

What is the way forward?
Considering the history of the opioid crisis in the US, and what researchers now know about how these drugs act in the body and brain, Ballantyne advocated for a change in expectations for the future of pain therapy: rather than use opioid drugs to treat pain, non-drug approaches should be encouraged instead. Many of those approaches do work, she said, and they do so by engaging the endogenous opioid system, which has powerful pain-relieving effects all of its own.

Put another way, Ballantyne argued that when it comes to treating chronic pain, perhaps it’s time to look from within—to what nature has already provided—rather than from without.

Editor’s note: RELIEF’s news coverage is editorially independent of its publisher, IASP. All editorial decisions about our reporting on IASP activities are made solely by the RELIEF editors.