Why are Opioids Addictive?

The U.S. has a serious opioid problem. In 2014, an estimated 2 million Americans abused opioids, and 91 Americans die every day from an opioid overdose.

Prescribing behavior plays a big role in exposure and often fuels the addiction. Plus, there’s an ample supply to take from. The number of opioids prescribed each yearhas nearly quadrupled since 1999.

Many people are abusing opioids, and many people are dying from them, but why are opioids addictive? What function in the brain makes us susceptible?

We spoke to Patrick Rothwell, Ph.D., assistant professor in the Department of Neuroscience in the Medical School and MnDRIVE neuromodulation scholar, to answer those questions. He specializes in the neuroscience of addiction.

How do opioids work?

Opioids mimic natural highs caused by chemicals synthesized normally in our own bodies. These “endogenous” opioids are naturally released when we’re happy, or seeing a loved one, or exercising, Rothwell says.

Opiate-based painkillers activate the same receptors. These opioid receptors are found throughout the body, including the brain and the spinal cord. Activation of opioid receptors in different locations leads to the diverse behavioral effects of opiate-based painkillers, such as pain relief, constipation and euphoria.

How do opioids become addictive?

“Opioids target a part of the brain associated with reward and reinforcement processes,” Rothwell said.

Opioid receptor activation increases levels of dopamine in the brain. Dopamine and opioids work together to generate the “high” and encourage drug-seeking behavior. 

Over time the body builds up a tolerance, requiring a higher dose to relieve pain and get high. Prolonged use of opioids can even change the signaling pathways engaged by these drugs.

“If they’re turned on for a long time, feedback mechanisms kick in to constrain activation. That feedback mechanism is what leads to dependence and causes withdrawal.”

Eventually, the body becomes dependent on the presence of an opioid to function normally. Without it, people experience withdrawal which can include vomiting, diarrhea, fatigue, severe sweating and anxiety.

Let’s get into the weeds.

The part of the brain housing reward and reinforcement behavior is called the nucleus accumbens. The nucleus accumbens is home to dopamine receptors: D1 and D2. D1 fuels reward behavior, while D2 establishes aversion. Opioids cause release of dopamine in the nucleus accumbens, which binds to the D1 and D2 receptors and promotes reward.

A recent UMN study from researcher Mark Thomas, Ph.D., associate professor in the Departments of Neuroscience and Psychology, found repeated opioid exposure increased activity to the reward receptor and inhibited the control (or aversion) receptor.

For someone using opioids, this means the brain produces feelings of euphoria when using drugs and suppresses the ability to stop drug use. Someone can even be in recovery, drug-free, and still experience the reward-reinforcement loop because the brain is activated by triggers alone.

Are other prescription drugs addictive that way?

“You don’t get the same physical dependency with other classes of drugs,” Rothwell said.

To put it simply, they’re different. They use different receptors and pathways. Painkillers like ibuprofen or acetaminophen target the peripheral nervous system, comprised of nerves located outside the spinal cord and brain. In addition, the mechanism for pain relief is different. These OTC drugs provide anti-inflammatory benefits without activating opioid receptors.

MORE: How other UMN researchers are developing new non-addictive painkillers and drugs that don’t reach the brain.