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Designing Much less Addictive Opioids, By means of Chemistry

By Aaron W. Harrison, Austin College

What if there was a way for pain sufferers to get the pain relieving power of opioids without the addictive side effects?

Opioids are one of the most powerful pain relievers available, but millions of Americans struggle with prescription opioid abuse after becoming addicted to the feelings of calm and euphoria they also induce. However, new research suggests that there might be a way to chemically tailor opioids to reduce their potential for addiction.

The first wave of the opioid epidemic in the US began in the 1990s. By 2015, approximately 11.5 million Americans struggled with prescription opioid abuse. The Centers for Disease Control and Prevention estimates that nearly 500,000 people died from an opioid overdose between 1999 and 2019. Recent reports have shown that this ongoing health crisis only got worse during the COVID-19 pandemic. The US hit a record 93,000 deaths from overdose in 2020, a 29% increase from the previous year.

Many people with opioid addiction report using these drugs to relieve physical pain: Treating chronic pain is a leading cause of opioid abuse. However, there are currently no equivalent drugs that can provide the same level of pain relief without the potential risk of addiction.

However, a less addictive opioid could be an important tool in combating the opioid epidemic. I’m a physical chemist interested in this problem, and my research group used computational chemistry to study how opioids like morphine can be remodeled to target specific areas of pain without affecting the brain.

In an attempt to develop a less addictive pain reliever, researchers made more forms of addictive opioids.

The biochemistry of opioids

There are many different classes of opioids that differ in their chemical structure. However, all opioids contain the same type of chemical group that determines their biochemical activity. Morphine, oxycodone and hydrocodone belong to the same main class of epoxymorphinan opioids and have almost identical chemical structures.

Structures of epoxymorphinan structures

Morphine, oxycodone, and hydrocodone belong to the same class of opioids and have similar structures.
Aaron Harrison, CC BY-ND

Fentanyl, on the other hand, belongs to the class of phenylpiperidines of the opioids and looks very different.

Chemical structures of morphine and fentanyl

Morphine and fentanyl have different chemical structures, but share a nitrogen group that has a similar chemical reaction in the bloodstream.
Aaron Harrison, CC BY-ND

The chemical structures of these molecules will be a bit of a mystery if you’ve never taken an organic chemistry course before. However, we can simplify the picture by focusing on the similarities. Both molecules contain a nitrogen that is part of a so-called amine group. This group can become positively charged through a chemical reaction that occurs in water-based environments such as the bloodstream.

Morphine reaction with water to produce active opioid.

Neutrally charged morphine undergoes a chemical reaction in water to become a positively charged, biochemically active compound.
Aaron Harrison, CC BY-ND

This positively charged structure is the biochemically active form of the opioid – it has no effect on your body until it receives this positive charge. The positive charge of the nitrogen helps these drugs attach to the target area where the pain originates and provides relief.

The typical acidity of the body of the average person provides ideal conditions for a positive charge of morphine and fentanyl. This means that almost all of the drug consumed is biochemically active throughout the body. Whether in the brain or at the injury site, cells all over the body will feel the effects of the drug.

Make opioids less addicting

Many of the addictive properties of opioids are due to the feeling of calm and euphoria they induce in the brain. However, for conditions like arthritis and wound and post-operative pain, these drugs only need to target the diseased or injured areas of the body to relieve the pain. The question the researchers are asking is whether it is possible to limit the effects of opioids to specific areas of the body without affecting the brain.

A recently proposed solution focuses on the difference in acidity between injured and healthy tissues. Injured tissue is more acidic than healthy tissue due to a process known as acidosis, in which lactic acid and other acidic by-products produced by damaged tissue build up. This means that an opioid could potentially be modified so that it is positively charged and active only in injured tissue, while remaining neutral and inactive in normal tissue. The drug would only be biochemically active if the acid content was higher than that found in healthy tissue.

This theory was first explored with fentanyl. Researchers found that introducing a fluorine (F) atom into the amine group near the nitrogen can decrease the acid range in which fentanyl is active, making it less likely to be active during the body’s normal acid levels.

Chemical structure of fluorinated fentanyl

Adding a fluorine atom to fentanyl can reduce the likelihood that it will be biochemically active in healthy body tissues.
Aaron Harrison

The addition of fluorine to fentanyl demonstrated increased opioid activity in the more acidic conditions of injured tissue compared to healthy tissue. This meant that the drug was only “turned on” in parts of the body that needed pain relief. In addition, it showed a decrease in serious side effects associated with opioids, such as addictive potential and abnormally decreased respiratory rate, while continuing to provide pain relief.

My colleagues and I recently expanded this framework to include morphine. We have shown that similar fluorine substitutions can also tailor the active acid range of morphine to specifically target injured tissue. Given that molecules of the same class of opioids as morphine share similar structures, we believe this approach would work for other opioids such as hydrocodone and oxycodone as well.

Chemical structure of fluorinated morphine

Adding a fluorine atom to morphine can reduce the likelihood that it will be biochemically active in healthy body tissues.
Aaron Harrison, CC BY-ND

Effective pain management without exposing patients to risk of addiction remains a major public health problem. This approach has only been tested in laboratory settings and may not be used in pharmacies for some time, if at all. But chemically altering existing opioids is a promising avenue for developing drugs that relieve pain without causing addiction.

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Aaron W. Harrison, Assistant Professor of Chemistry, Austin College

This article was republished by The Conversation under a Creative Commons license. Read the original article.

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