The hunt for new painkillers that will end the opioid crisis


When Krystin Zeller was 19, in 2007, she started taking Vicodin to treat pain after a car accident. In the first month, she felt withdrawal symptoms, and within six months, she knew she was addicted, soon turning to heroin to get the same relief. Eventually, she was arrested and went to rehab. She’s been clean since 2013, she says, avoiding taking painkillers even when doctors have tried to foist them on her. “Pain can’t kill you. Prescription narcotics can,” Zeller told Vocativ.

Zeller lived to tell the tale of her spiral into addiction, but not all do. The opioid epidemic, fueled by decades of overprescription of opioid painkillers, claimed33,000 American lives in 2015. The number of deaths from heroin overdosetripled between 2000 and 2014, and it only seems to be growing.

Now, as regulators such as the Centers for Disease Control push doctors to cut down on the number of opioids they prescribe, researchers and companies are looking for alternative ways to treat pain — both by developing new kinds of painkillers and by shifting pain remedies away from drugs altogether. The larger goal is treatments that are safer and less susceptible to abuse, ultimately saving lives.

RELATED: Opioids affect health in a multitude of ways

Opioid painkillers capitalize on our body’s natural pain-relief system. We all have a series of naturally produced keys (“ligands”) and keyholes (“receptors”) that fit together to switch on our brain’s natural reward system — it’s the reason we feel good when we eat a good meal or have sex, for example. But opioids mimic the natural keys in our brain — yes, we all have natural opioids! When they click in, we can feel an overwhelming sense of euphoria.

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Opioid painkillers can have effects similar to heroin and morphine, especially when taken in ways other than prescribed by a doctor.

When prescription painkillers act on our brain’s pleasure and reward centers, they can make us feel good. More importantly, though, they can work to reinforce behavior, which in some people can trigger a repeated desire to use.

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You may also feel sleepy.

Opioids act on multiple brain regions, but when they go to work in the locus ceruleus, a brain region involved in alertness, they can make us sleepy. Why? The drugs essentially put the brakes on the production of a chemical called norepinephrine, which plays a role in arousal.

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Your skin may feel flushed and warm.

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You’ll begin to feel their effects 10 to 90 minutes after use, depending on whether they’re taken as directed or used in more dangerous ways.

Some drugmakers design versions of their medications to deter abuse. Extended-release forms of oxycodone, for example, are designed to release slowly when taken as directed. But crushing, snorting, or injecting the drugs can hasten their effects.

It can also be deadly. Between 2000 and 2014, nearly half a million Americans died from overdoses involving opioid painkillers and heroin, a report from the US Centers for Disease Control and Prevention found. The most commonly prescribed painkillers were involved in more overdose deaths than any other type of the drug.

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Your breathing will slow as well.

Depending on the method used, the effect can last anywhere from four to 12 hours.

For severe pain, doctors typically prescribe opioid painkillers like morphine for a period of four to 12 hours, according to the Mayo Clinic. Because of their risks, it’s important to take prescription painkillers only according to your physician’s specific instructions.

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Overdosing can stop breathing and cause brain damage, coma, or even death.

2014 report from the American Academy of Neurology estimates that more than 100,000 Americans have died from prescribed opioids since the late 1990s. Those at highest risk include people between 35 and 54, the report found, and deaths for this age group have exceeded deaths from firearms and car crashes.

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Combining them with alcohol or other drugs — even when taken according to the directions — can be especially deadly.

Since they slow breathing, combining opioid painkillers with other drugs with similar effects can drastically raise the chances of accidental overdose and death.

Yet they’re often prescribed together anyway, according to the National Institute on Drug Abuse. “Unfortunately, too many patients are still co-prescribed opioid pain relievers and benzodiazepines [tranquilizers],” the institute said. In 2011, 31% of prescription opioid-related overdose deaths involved these drugs.

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Abusing opioid painkillers has been linked with abusing similar drugs, like heroin.

A CDC report found that people who’d abused opioid painkillers were 40 times as likely to abuse heroin compared with people who’d never abused them. The National Institute on Drug Abuse says that close to half of young people surveyed in three recent studies who’d injected heroin said they’d abused prescription painkillers before they started using heroin.

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You may also develop a tolerance for the drugs so that you need more to get the same effect over time.

Tolerance to opioid painkillers happens when the brain cells with opioid receptors — the keyholes where the opioids fit — become less responsive to the opioid stimulation over time. Scientists think that this may play a powerful role in addiction.

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Suddenly stopping the drugs can result in withdrawal symptoms like shakiness, vomiting, and diarrhea.

Taking prescription painkillers for an extended period increases the likelihood that your brain will adapt to them by making less of its own natural opioids. So when you stop taking the drugs, you can feel pretty miserable. For most people, this is uncomfortable but temporary.

But in people who are vulnerable to addiction, it can be dangerous because it can spurn repeated use.

“From a clinical standpoint, opioid withdrawal is one of the most powerful factors driving opioid dependence and addictive behaviors,” Yale psychiatrists Thomas Kosten and Tony George write in a 2002 paper in the Journal of Addiction Science  Clinical Practice.

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“We have to take care of people in pain, and opiates aren’t the solution,” said Dave Thomas, a program officer in service and prevention research at the National Institute on Drug Abuse (NIDA). “We do need more options than opioids. The trick is to get the right people the right drugs.”

Pain isn’t an easy condition to treat. It involves many different systems in the body, and an ancient, complex circuitry that notifies the brain when a body part is being damaged. Sometimes, though, that circuitry can go haywire, causing pain when the body is not peril. For each of the 100 million Americans with chronic pain, it can be nearly impossible to know just which systems are the cause. Pain is so complex, Thomas said, that “to find one magic bullet that will stop it completely is difficult.”

Opioids are an appealing treatment because they can treat pain no matter its type or source. Once drugs such as oxycodone and morphine are in the body, they attach to one or two of four special receptors, collectively called opioid receptors, found on nerve cells. Because these cells are in organs all over the body, opioids affect the whole system. But there aredownsides— those receptors are also linked to feelings of pleasure and reward, so people can quickly form a physiological and psychological dependence. In high doses, opioids can cause death by slowing or stopping breathing and the heart. The pharmaceutical company that created OxyContin, the first opioid painkiller to be approved by the Food and Drug Administration (FDA), wasfined $600 million afterdeceiving regulators on the drug’s addictive qualities, fueling decades of overprescription.

Researchers are working on tweaking opioids to provide more painkilling power with fewer negative side effects and potential for abuse. Some, called abuse-deterrent opioids, simply change the formulation to make the pills harder to crush and snort or inject, but it’snot yet proven if these changes do in fact cut down on abuse as intended. Other new drugs are formulated to target different opioid receptors, which means they may be less effective at alleviating pain but substantially less addictive. These drugs are early in development by pharmaceutical companies and academic scientists, and so far there are indications that they could be less addictive than existing painkillers like morphine, at least in studies done on animals.

But drugs that target the same receptors can’t improve very much on existing painkillers, saidLinda Watkins, a psychology professor at the University of Colorado at Boulder. A slew of drugs in various stages of development target one or more of the thousands of receptors that might be involved in pain. Compared to opioids, these treatments are often specific to a particular part of the body — joints like the knees or shoulders, or the gastrointestinal tract — and are delivered by injection or a topical cream. But, importantly, many of these new compounds reduceinflammation, the body’s immune response that is often involved in chronic pain conditions.

In the past few years, federal agencies such as the NIH and the Veterans Association have started allocating more money for research into new pain treatments. “Ideally, we fund approaches that result in less pain and a better quality of life, while relying less on opioids,” Thomas says. Making less addictive pain treatments in particular is a very high priority, he adds. “At this point, funding of these initiatives has relied on agency allotted budgets, where we have shifted funds to address this important issue.”

But getting these alternatives to market has proven challenging. Painkilling drugs, no matter how promising, fail often — 33 would-be pain therapies failed in clinical trials between 2009 and 2015, according toBloomberg. Most don’t even get that far, to human testing.

“A lot of really innovative stuff reaches ‘Death Valley’—it’s a good idea, it has good rodent data, and it’s on the edge of a clinical trial [testing it in humans], but it needs millions of dollars in funding,” Watkins said. It’s very difficult to get a pharmaceutical company or venture capitalist firm to invest without data showing that the treatment works in humans, she says. From a business perspective, opioids are a much safer bet.

Watkins knows this first-hand. Over the past 25 years, Watkins has been developing painkilling compounds that affect receptors on cells called glia, found all over the body and seem to play a role in connecting the immune system to the brain. If researchers can create a compound that quiets signals of inflammation that glial cells transmit to the brain, they can reduce the sensation of pain in a particular area of the body. Watkins and her collaborators have done just this — a single injection of the compound can ease joint pain for months in rats anddogs with osteoarthritis. They have licensed the technology to a small pharmaceutical company, called Xalut Therapeutics. Soon, Watkins and her collaborators plan to test it on humans, but it’s been a long road.

Other startups are turning to painkilling compounds found elsewhere in the natural world. Vitality Biopharma has created a drug that targets cannabinoid receptors (the same ones affected when a person smokes marijuana) to treat gastrointestinal disorders and, eventually, neurological disorders. These receptors work in concert with opioid receptors to reduce pain, but don’t have the same addictive effects as do opioids, said Robert Brooke, the company’s CEO. This month,Centrexion Therapeutics completeda clinical trial for a drug with an active compound derived from chili peppers to treat joint pain. Researchers have discovered other chemicals, found inspider orsnake venom, that could soon be developed into painkillers.

Some researchers are looking beyond drugs; a growing class of devices to treat pain are receiving FDA approval and hitting the market. Most of these work by sending low-level shocks into the nerves to interrupt electrical signals transmitting sensations of pain to the brain.Quell, a device that sends electricity through the skin to treat pain anywhere from the joints to the lower back, received approval in January and is on sale;Stimwave makes a Miniature Peripheral Nerve Stimulator, a tiny implanted device to designed to minimize chronic pain, which was approved in March.

But depending on a patient’s specific painful condition and the device he or she is using, devices often have to be partnered with other treatments to provide substantial relief. “There is probably not one device that will help someone completely,” Thomas said.

Ultimately, patients might benefit most from treatments that don’t involve drugs or devices. A growing contingent of healthcare professionals encourage doctors to turn to tried-and-true opinions like cognitive behavioral therapy or physical therapy to help patients manage their pain. These techniques are often less appealing to patients because they’re more difficult and time-consuming than simply popping a pill. But they offer fewer side effects that might help patients live richer lives. Better educating clinicians, who are often not given sufficient training about how to treat a condition as complex as pain, can help make that happen, Thomas says.

Zeller has found relief for her chronic pain with exercise, weight loss, and aspirin. She vows she will never take another painkiller, no matter its purported non-addictive qualities, for fear of reigniting her own addiction. Nothing will ever convince her otherwise.

Scientists are also working on new ways to characterize or objectively measure pain with techniques such asbrain wave detection or evengenetics. These measurements would be critical to popularize new pain treatments that might be specific to a type of pain or a certain part of the body, and would also prevent clinicians from giving opioids to patients who are likely to abuse them.

Someday, these new treatments may become doctors’ go-to to treat patients’ pain. But for now, healthcare workers are left with the difficult task of treating pain — and dependence on opioids — with many of the same tools they’ve had for decades.

“The better we take care of people in pain, the more of a dent we will put in the crisis,” Thomas said.

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