In medicine, our strongest painkillers are Opioid based. These work quite well, however, it’s well known about the addictive effects that the drugs have. In an effort to start to work against opioid addiction while keeping up the effectiveness, researchers are taking the time to seek alternative medicines to test.
Last year, Joan Peay slipped on her garage steps and smashed her knee on the welcome mat. Peay, 77, is no stranger to pain. The Tennessee retiree has had 17 surgeries in the last 35 years — knee replacements, hip replacements, back surgery. She even survived a 2012 fungal meningitis outbreak that sickened her and hundreds of others, and killed 64. This knee injury, though, “hurt like the dickens.”
When she asked her longtime doctor for something stronger than ibuprofen to manage the pain, he treated her like a criminal, Peay says. His response was frustrating: “He’s known me for nine years, and I’ve never asked him for pain medicine other than what’s needed after surgery,” she says. She received nothing stronger than over-the-counter remedies. A year after the fall, she still lives in constant pain.
Just five years ago, Peay might have been handed a bottle of opioid painkillers for her knee. After all, opioids — including codeine, morphine and oxycodone — are some of the most powerful tools available to stop pain.
Hitting opioid receptors in the peripheral nervous system keeps pain messages from reaching the brain. But opioids can cause problems by overstimulating the brain’s reward system and binding to receptors in the brain stem and gut.
But an opioid addiction epidemic spreading across the United States has soured some doctors on the drugs. Many are justifiably concerned that patients will get hooked or share their pain pills with friends and family. And even short-term users risk dangerous side effects: The drugs slow breathing and can cause constipation, nausea, and vomiting.
A newfound restraint in prescribing opioids is in many cases warranted, but it’s putting people like Peay in a tough spot: Opioids have become harder to get. Even though the drugs are far from perfect, patients have few other options.
Many drugs that have been heralded as improvements over existing opioids are just old opioids repackaged in new ways, says Nora Volkow, director of the National Institute on Drug Abuse. Companies will formulate a pill that is harder to crush, for instance, or mix in another drug that prevents an opioid pill from working if it’s crushed up and snorted for a quick high. Addicts, however, can still sidestep these safeguards. And the newly packaged drugs have the same fundamental risks as the old ones.
The need for new pain medicines is “urgent,” says Volkow.
Scientists have been searching for effective alternatives for years without success. But a better understanding of the way the brain sends and receives specific chemical messages may finally boost progress.
Scientists are designing new, more targeted molecules that might kill pain as well as today’s opioids do — with fewer side effects. Others are exploring the potential of tweaking existing opioid molecules to skip the negative effects. And some researchers are steering clear of opioids entirely, testing molecules in marijuana to ease chronic pain.
Humans recognized the potential power of opioids long before they understood how to control it. Ancient Sumerians cultivated opium-containing poppy plants more than 5,000 years ago, calling their crop the “joy plant.” Other civilizations followed suit, using the plant to treat aches and pains. But the addictive power of opium-derived morphine wasn’t recognized until the 1800s, and scientists have only recently begun to piece together exactly how opioids get such a stronghold on the brain.
Opioids mimic the body’s natural painkillers — molecules like endorphins. Both endorphins and opioids latch on to proteins called opioid receptors on the surface of nerve cells. When an opioid binds to a receptor in the peripheral nervous system, the nerve cells outside the brain, the receptor changes shape and sets in motion a cellular game of telephone that stops pain messages from reaching the brain.
The danger comes because opioid receptors scattered throughout the body and in crucial parts of the brain can cause far-reaching side effects when drugs latch on. For starters, many opioid receptors are located near the base of the brain — the part that controls breathing and heart rate. When a drug like morphine binds to one of these receptors in the brain stem, breathing and heart rate slow down. At low doses, the drug just makes people feel relaxed. At high doses, though, it can be deadly — most opioid overdose deaths occur when a person stops breathing. And high numbers of opioid receptors in the gut — thanks in part to all the nerve endings there — can trigger constipation and sometimes nausea.
No matter how much I say I want to avoid opioids, half of my patients will get some kind of opioid. It’s just unavoidable.
— Christopher Wu
Plus, opioids are highly addictive. These drugs mess with the brain’s reward system, triggering release of dopamine at levels higher than what the brain is used to. Gradually, the opioid receptors in the brain become less sensitive to the drugs, so the body demands higher and higher doses to get the same feel-good benefit. Such tolerance can reset the system so the body’s natural opioids no longer have the same effect either. If a person tries to go without the drugs, withdrawal symptoms like intense sweating and muscle cramps kick in — the body is physically dependent on the drugs. Addiction is a more complex phenomenon than dependence, involving physical cravings so strong that a person will go to extreme lengths to get the next dose. Long-term users of prescription opioids might be dependent on the drugs, but not necessarily addicted. But dependence and addiction often go together.
Despite their risks, opioids are still widely used because they work so well, particularly for moderate to severe short-term pain.
“No matter how much I say I want to avoid opioids, half of my patients will get some kind of opioid. It’s just unavoidable,” says Christopher Wu, an anesthesiologist at Johns Hopkins Medicine.
In the late 1990s and early 2000s, more doctors began doling out the drugs for long-term pain, too. Aggressive marketing campaigns from Purdue Pharma, the maker of OxyContin, promised that the drug was safe — and doctors listened. Opioid overdoses nearly quadrupled between 2000 and 2015, with almost half of those deaths coming from opioids prescribed by a doctor, according to data from the U.S. Centers for Disease Control and Prevention.
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Opioid prescriptions rose in the United States throughout the 1990s and early 2000s. Physicians have begun to back off in the last few years.
Source: IMS Health
Opioid prescriptions have dipped a bit since 2012, thanks in part to stricter prescription laws and prescription registration databases. U.S. doctors wrote about 30 million fewer opioid prescriptions in 2015 than in 2012, data from IMS Health show. But restricting access doesn’t make pain disappear or curb addiction. Some people have turned to more dangerous street alternatives like heroin. And those drugs are sometimes spiked with more potent opioids such as fentanyl (SN: 9/3/16, p. 14) or even carfentanil, a synthetic opioid that’s used to tranquilize elephants. Overdose deaths from fentanyl and heroin have both spiked since 2012, CDC data reveal.
A sharper target
Scientists have been searching for a drug that kills pain as successfully as opioids without the side effects for close to a hundred years, with no luck, says Sam Ananthan, a medicinal chemist at Southern Research in Birmingham, Ala. He is newly optimistic.
“Right now, we have more biological tools, more information regarding the biochemical pathways,” Ananthan says. “Even though prior efforts were not successful, we now have some rational hypotheses.”
Scientists used to think opioid receptors were simple switches: If a molecule latched on, the receptor fired off a specific message. But more recent studies suggest that the same receptor can send multiple missives to different recipients.
The quest for better opioids got a much-needed jolt in 1999, when researchers at Duke University showed that mice lacking a protein called beta-arrestin 2 got more pain relief from morphine than normal mice did. And in a follow-up study, negative effects were less likely. “If we took out beta-arrestin 2, we saw improved pain relief, but less tolerance development,” says Laura Bohn, now a pharmacologist at the Scripps Research Institute in Jupiter, Fla. Bohn and colleagues figured out…
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