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The Science of Addiction: How Opioids — and Environment — Change the Brain

In March, Stephen Loyd was scrolling through Google images for a PowerPoint presentation on addiction when a picture of a bottle of Percocet pills triggered a powerful craving.

His mouth watered. His hand trembled. He couldn’t move the computer mouse.

When it happened, Loyd was in his office on the sixth floor of a government building in downtown Nashville, where he serves as medical director for Substance Abuse Services for the state of Tennessee, one of the states hardest hit by the opioid epidemic.

And he has been clean 13 years.

COMPLETE COVERAGE: The science of opioids

That’s how powerful opioid cravings are, Loyd said. And cravings are the primary reason it’s so hard to treat opioid addiction.

“The reason people relapse is the cravings,” Loyd said. “The cravings are persistent for the rest of your life. … I always wonder, when I tell this, if people get nervous. I’m the medical director for the whole state. The medical director for the state of Tennessee still gets cravings for opioids? He does.”

How opioids trick the brain

The human brain is designed to reward you with feelings of pleasure when you engage in activities that benefit our species: eating, exercising, sex. When part of the brain — the ventral tegmental area — is signaled that you’re doing these things, it triggers another part of the brain — the nucleus accumbens — to release the chemical dopamine. Brain cells sensitive to dopamine receive it and generate a feeling of pleasure. Meanwhile, other parts of the brain form a memory of what happened to produce that pleasurable feeling.

Opiate drugs, which come from the opium poppy flower, and synthetic, or man-made, opioids also can trigger that brain process in the mesolimbic system. The drugs attach to certain specialized proteins on the same receptor brain cells where the pleasure-causing chemicals the body naturally makes normally attach. So can other drugs, including alcohol — but the body seems to develop a tolerance to opioid drugs more quickly.

That is, it develops a tolerance for the drugs’ abilities to relieve pain or produce pleasure, requiring an increasingly higher amount to fire up the process that produces dopamine, said neuropsychiatrist Dr. Richard Gibson, an addiction specialist who practices, teaches and conducts research at the University of Tennessee Medical Center in Knoxville.

However, Gibson said the body doesn’t develop a tolerance to the amount of drugs needed to depress the respiratory system — which is how most opioid users fatally overdose.

Gibson said opioids can physically change the structure of the brain. That concept of “plasticity” was foreign when he went through medical school in the 1960s.

“We thought the brain was unchanging,” Gibson said. “It turns out the brain can remodel itself quite well in a lot of circumstances” — for better or worse.

Dropped signals, bad judgment

Among the changes that can occur is a disconnect between the part of the brain responsible for insight and judgment — the prefrontal cortex — and the mesolimbic “reward center” that triggers the release of dopamine, Loyd said.

Ordinarily, the prefrontal cortex sends signals to that reward center. The result: the ability to use judgment to restrain bad impulses.

“We do it all the time — we kind of play through scenarios and pick the one that has the most benefit and the least consequences,” Loyd said.

But studies have suggested drug abuse not only could lower the level of the chemical used to transmit those signals, but also could damage the particular circuit that carries the signals from the prefrontal cortex to the reward center. In fact, Loyd said some studies suggest those connections stop developing at the age of first drug use — “so you can have somebody who’s 35 years old, and they’re making decisions like a 12-year-old.”

Those connections can re-form, Loyd said, but it takes time — about 18 months to two years for most people.

That’s why he argues that detox alone — getting addicts over the hump of terrible withdrawal symptoms, which range from a few days to a few weeks, depending on the drug — isn’t enough to ensure they’ll stay clean. Putting people through detox and then turning them back out on the streets is like “sticking them out there with a half a brain,” he said. Since the prefrontal cortex still isn’t functioning normally, “they’re driven solely by rewards, they’re having cravings, and they’re going to relapse 99 times out of 100.”

Why do doctors and pilots do better?

For years, Loyd wore rubber bands around his wrists like bracelets. Few people knew their purpose — it was so he could “snap” his wrist if he felt a drug craving coming on, interrupting the “loop” of fixating on the drug, how it would make him feel and how to get it. Having interrupted the loop, he could then move through the process he knew would keep him from seeking a high: call a buddy, talk about the impulses, engage the prefrontal cortex to remind him of all he had to lose.

Loyd didn’t automatically learn this process. It was, in a sense, a byproduct of his profession. At the time he became addicted, Loyd was a practicing internal medicine physician. After detoxing in a major research hospital, he went into a 90-day inpatient addiction treatment program that accepted only medical professionals and fully prepared him to deal with cravings afterward, teaching him to recognize the onset and reach out for help. It came with five years of aftercare.

In contrast, most people who do manage to get expensive inpatient treatment get, at most, 28 days, Loyd said. Even those people are a tiny fraction of people who need it. A 2015 report by the federal Substance Abuse and Mental Health Services Administration estimated only 10.8 percent of the people who needed substance abuse treatment got any — inpatient, outpatient or even detox.

In various studies, the five-year sobriety rate for opioid addicts ranges from less than 10 percent to about 30 percent. But among doctors and airline pilots, who get intensive inpatient treatment and aftercare, it’s 75 percent to 90 percent, Loyd said.

“We don’t do that well with strep throat!” he said.

Pilots and physicians are examples of high-pressure, high-paying professions. While they may have more resources than average people, they’re also harder to replace — so there’s a vested interest in returning them to the same jobs in which they might have become addicted.

In the case of commercial airline pilots, the Federal Aviation Administration oversees an intensive peer-reported treatment program, the Human Intervention Motivation Study (HIMS), which began in the 1970s, then sponsored by the Air Line Pilots Association International labor union and funded by the National Institute for Alcohol Abuse and Alcoholism. Through the program, most pilots get about a month of inpatient treatment and about three years of follow-up recovery treatment, along with several years of close monitoring for relapse.

For doctors, most states — including Tennessee — have a physician health program that intervenes when doctors are facing mental health or substance abuse issues. The doctor is evaluated, and case managers in the physician health program make recommendations for treatment; the doctor pays for the recommended treatment. After treatment, the physician health program and treatment program make ground rules for the doctor’s re-entry into practice, establishing a contract with the doctor based on their recommendations. Follow-up care usually lasts about five years.

“So, we know the model” for long-term sobriety, Loyd said.

What’s lacking is the funding to provide that type of intensive inpatient treatment to the broader population of addicts.

‘Leveling the field’ with medications

That’s where medication-assisted therapy comes in, Loyd said: “It levels the playing field.”

Methadone, a long-acting narcotic painkiller, fits into the same brain receptors as opioids but doesn’t produce the euphoric “high” the opioid drugs do. It also can block opioids from attaching to the receptors, if a person relapses and takes an opioid after having taken methadone.

Naltrexone, approved to treat opioid addiction in 1984 and alcohol addiction in 1994, binds to the receptors and blocks them altogether so that opioids can’t attach. Because naltrexone doesn’t activate the receptors at all, though, it won’t prevent withdrawal symptoms, and patient compliance with taking it regularly has historically been low. In recent years, naltrexone has been available in an injection — Vivitrol — that’s taken once a month.

Buprenorphine — sometimes combined with naloxone in Suboxone — fits into the opioid receptors, but it’s not a perfect fit, so the receptor only partially “fires.” The body is tricked into thinking it has opioids, but buprenorphine won’t produce a euphoric high or depress the respiratory system.

The three drugs, available by prescription only, are doled out under a doctor’s supervision. Treatment can be expensive — around $500 a month for cash-paying patients to get an office visit and fill the prescription.

While many people “have very strong moral feelings” against using replacement drug therapy with someone who’s addicted, “there’s a lot of evidence it’s one of the more effective harm-reduction strategies in all of medication,” Gibson said.

At one year after starting medically managed treatment, Gibson said, three-quarters or more of opioid addicts haven’t relapsed; for an abstinence-only program, the success rate is less than 20 percent.

The medications’ “utility is, they quell cravings, and now you’ve got time to hold people in treatment and teach them the skills they need to manage cravings and stay clean going forward,” Loyd said.

Managing cravings is key to long-term success. Powerful cravings can happen suddenly after years of sobriety, the brain reacting as though the body will go into withdrawal if it doesn’t get opioids, Gibson said.

Scientists have investigated whether a trace of opioids could be stored somewhere in the brain, emerging randomly, but “every evidence we have suggests this is not possible,” he said.

Instead, most researchers think a cued reminder “triggers” a physical craving — an image, sound, scent. When scientists put a crack addict in a scanner that looks at brain chemistry and flashed a photo of a crack pipe for 33-thousandths of a second — too quickly for him to even be aware he saw it — the image showed a definite reaction in the mesolimbic reward center of the brain.

“It’s like a ticking time bomb for some people,” Gibson said.

Genetics + environment = increased risk

Addictionology isn’t an exact science. Scientists aren’t sure yet, for example, what role genetics play, but it’s clear having a family history of addiction may predispose a person to become addicted.

Environment, too, plays a big part, especially stressors. Men are more likely than women to become addicted to opioids, but scientists don’t know if that’s because of a physical difference in the way the body reacts to drugs, a psychological difference in how men and women handle stress or temptation, or some combination.

Several studies suggest up to 75 percent of people who abuse opioids were victims of physical or sexual abuse, with women more likely than men to have been abused.

The landmark 1995 CDC-Kaiser Permanente Adverse Childhood Experiences Studylinked adverse childhood experiences — ACEs — directly with significantly increased risk of heart disease, cancer, mental illness, violence, suicide — and addiction.

ACEs can include physical, emotional and sexual abuse; physical and emotional neglect; living with a family member with addiction or other mental illness; living through parents’ divorce or separation; having an incarcerated family member; witnessing a family member being abused; being homeless; being bullied or living in an unsafe neighborhood or a war zone; and being in the foster-care or juvenile detention systems.

The study found that the more types of adversity a child experienced, the higher the risk of these physical and mental issues. People who experienced five or more types of trauma were seven to 10 times more likely to use illegal drugs — including injecting them — and to report being addicted.

Dr. Daniel Sumrok, director of the Center for Addiction Sciences at the University of Tennessee Health Science Center’s College of Medicine in Memphis, said the “trauma of childhood” absolutely can cause “neurobiological changes.” He estimates 90 percent of his clients have had three or more ACEs.

In two outpatient clinics, Sumrok combines medication-assisted therapy with therapy to address those childhood traumas. Drug use, he believes, is actually “ritualized compulsive comfort-seeking”; part of his job is to help patients replace it with a safer, legal coping behavior.

Studies suggest that chronic stress during childhood can physically change the developing brain, shrinking the parts that process emotions, manage stress, control impulses, weigh decisions and deal with fear. As a result, as adults, children who had ongoing traumatic experiences may have more fear and anxiety related to even minor stressors, as well as more susceptibility to depression and mood disorders.

Sumrok, an Army veteran himself, spent the early part of his career researching the symptoms of post-traumatic stress disorder — including substance abuse — in Vietnam veterans, eventually concluding it’s not a “disorder” but rather a normal learned response to trauma.

Gibson was in the U.S. Navy when Veterans Affairs and Department of Justice began preparing for an expected onslaught of soldiers returning home from Vietnam addicted to heroin. Heroin was easy to get in Vietnam, and the government knew soldiers were taking it: Around 20 percent of returning soldiers said they were addicted.

Turns out, “when people were not in Vietnam anymore, and they weren’t in danger of being killed every day … the need for opioids was pretty much gone,” Gibson said. “People had some mild effects, but nothing like the degree of addiction that was thought to be present. … This led to a lot of insights into opioid addiction” — specifically, the impact of changing addicts’ environment and routine to help them get clean.

Addiction is as much a social problem as a scientific one, Loyd said. Sending a detoxed addict back into the situation that led to addiction is certain to backfire. The numbers bear out the need for follow-up, he said. An opioid addict who stays clean for one year has a 10-18 percent chance of making it to 15 years of sobriety.

“If you can get them to five years (clean), though, that jumps up to 65 percent,” he said. “It’s a dramatic difference. … The key is keeping them engaged in treatment.”

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