By Amy Baxter, MD 

At a recent scientific conference on narcotics, a researcher mused, “Honestly, opioids make me feel gross. I don’t see how anyone could get addicted.” This is a little like a doctor in the delivery end of a needle saying, “Honestly, you’re a wimp. This doesn’t hurt.” Both examples reveal a lack of empathy and a fundamental misunderstanding of current neuroscience.

The contributions or fear, reward, fight, and flight are a complicated mix of experience and genetics. Needle fear comes from a bad shot experience at a pre-logical developmental state, with a whiff of fainting-prone genetics. Opioid use disorder (OUD) flips the ratio, with such a strong genetic influence that it’s conflated with family environment. Neuroscience research untangling why some who are exposed to opioids become dependent is ongoing, with surprising implications for prevention.

1. Both emotional and physical pain areas are highly interconnected, allowing for quick punishment or reward responses to anything the human organism does. Otherwise, how does the brain learn? Reward switches in the brain release neurotransmitters that make you feel a certain way – dopamine for winning, serotonin for pleasure, and oxytocin for love. Some dopamine switches, called mu receptors, are morphine-activated and often overlap with the brain areas activated by pain. So morphine doesn’t stop pain, you just feel so rewarded you don’t mind.

2. Some people have more switches and need less morphine, while some people need more morphine to have sufficient reward for equivalent pain relief. The baseline array of reward switches depends on gender, age, previous experience, and genetics. Pain, both emotional and physical, can leave a persistent brain resting state that feels new pain strongly, needing more reward (opioids) to get to “I can handle it.”

3. As dopamine is the brain’s primary reward and behavior motivator, dopamine processing variations influence opioid effects. Some genetic subtypes are reward deficient – they get less of a kick from dopamine from daily activities. The theory is that when opioids activate their receptors, their experience goes beyond relief to euphoria. Many “mental health” issues now are felt to be associated with differences in dopamine and serotonin processing: thrill-seeking due to low dopamine responsiveness, depression from low dopamine output, etc.

4. The receptors’ behavior changes over time as well. After a short period of morphine exposure, some opioid dopamine receptors retreat into the cell to regroup. When less intense oral opioids are taken, the lower intensity and concentration can be compounded with the lack of switches for rewards, so home oral opioids have less impact than ibuprofen on pain.

5. Finally, different liver metabolism genes cause about 5-15% of people to quickly transform oral opioid forms into morphine. This “CYP 2D6” variation leads to more rewards up front but a faster return of pain. The 85% with different genes don’t turn the pills into morphine fast enough to help much with pain relief. However, nausea, constipation, sweating, and withdrawal aren’t affected.

So, “How can anyone get addicted?” There’s a lot to unpack. A colleague of mine developed an OUD after wrist surgery. There was stealing, lying, getting fired – the whole stereotype. Ignorantly, when he was in recovery, I asked him how on earth he let that happen. (You know, because post-operative opioids have always made me feel sluggish and nauseated …). To paraphrase:

“I always feel awkward and anxious, and I can’t ever relax. When I first took the pain pill, I felt awesome. I felt cool. I felt so great, and powerful, and happy, and worthy of being loved. How could you not want to keep feeling like that?”

Researchers call that feeling euphoria, and it is distinct from the relief of pain. A 2022 study asked people who had misused opioids (taken pills for a high) how they felt the first time. Those who went on to develop OUD had a very different experience.

Family history of addiction may relate to familial rapid activation or mu receptor euphoria, rather than generational environmental risk. People with the CYP 2D6 metabolism gene also have higher rates of smoking and alcoholism; the neurotransmitter reward in OUD, however, is orders of magnitude more intense. This is why 95% of successful OUD treatment requires medication, manipulating the “switches” to keep the reward pathways in check.

My best friend in high school died of a heroin overdose while I was away at college. I was appalled by her weakness and idiocy and stayed mad for two decades. I bet now that my chain-smoking friend, and the mother who gave her up for adoption, felt opioids differently than I do. I wish I could have told her, if nothing else, that a feeling of euphoria was a sign of risk. And I wish I could have understood then as I do now, her overdose resulted from a genetic disorder, not a moral failing. Rest in peace, Sue.

Amy Baxter is a clinical associate professor of emergency medicine at Augusta University, federally funded for neuromodulation research to reduce needle pain, multimodal low back pain, and opioid reduction. After attending Yale University and Emory Medical School, she completed her residency and a child maltreatment fellowship at Cincinnati Children’s Hospital Medical Center, an emergency pediatrics fellowship in Norfolk, Virginia, and a K30-NIH Clinical Research Certificate at UT Southwestern Medical Center.