Why Don't We Have Better Pain Drugs?

The answer involves both biology and economics, but the opioid crisis is forcing us to consider investing more in pain research.
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Pills.

Last year, I had my first experience with opioids. After a minor outpatient surgery, I went home with a 10-day supply of Norco, a combination of acetaminophen (the active ingredient in Tylenol) and the opioid hydrocodone. Nobody asked me if I wanted it—dispensing a Norco prescription was just a routine part of my post-surgical care. I didn't really need the meds, and the next day the pain from my surgery was largely gone. But I had the pills, and so I kept taking them. I did so because they brought great relief from some chronic pain stemming from a years-old shoulder injury—an injury that had nothing to do with my surgery.

For many people, this is a familiar story: a surgery, a prescription for opioids, and an excuse to keep taking the pills well after the reason for the original prescription no longer exists. A recent study looked at over 36,000 patients in the United States who had been prescribed opioids after surgery in 2013 and 2014, and found that routine, post-surgical opioid prescriptions often lead to longer-term opioid use. Significantly, the researchers found that long-term use of opioids "is not due to surgical pain but addressable patient level predictors," such as whether a patient is suffering from chronic pain. Fortunately for me, once my Norco prescription ran out, I was able to let it go without any trouble. But, according to the study, about 6 percent of surgery patients who are prescribed opioid painkillers will continue to use them months, or even years, later—putting these patients at risk for opioid addiction.

This scenario neatly captures the major underlying factors of the opioid abuse crisis in the U.S. We have a medical profession that freely prescribes opioids, in part because they are inexpensive and highly effective for acute pain; we also have a large population suffering from chronic pain (it affects one in three American adults, making it one of the most prevalent and costly health problems in the country). And even though the population seeking relief from chronic pain is a major driver of the opioid crisis, it is becoming increasingly clear that opioids are not very effective for chronic pain. However, there are few alternative treatments.

Tightening up doctors' opioid prescribing practices is a critical first step toward ending the current crisis of addiction and abuse. But over the longer term, we need better treatment for chronic pain, which, as anyone who has experienced it can tell you, is often utterly debilitating, even when there are no other major health problems involved. A new drug that packed the pain relief of opioids, but didn't carry the risk of addiction, would fill an enormous need. So why hasn't science come up with one?

The answer involves both biology and economics. As with many health problems, the underlying biology of pain is complicated. Pain is mediated by a diverse set of cellular pathways, and the specific pathways involved depend on the type of pain. Acute pain—what you feel when recovering from surgery—is different from chronic pain, like lower back pain that persists for years. Pain involves both the central nervous system, where opioid drugs act, as well as the site of injury, which is where drugs like aspirin work. Many of the molecular details of both pain and pain drugs are still poorly understood. Given the risky science, and the presence of cheap and fairly effective pain drugs already on the market, drug companies don't have much of an economic incentive to invest in the research and development of new painkillers.

A new drug that packed the pain relief of opioids, but didn't carry the risk of addiction, would fill an enormous need. So why hasn't science come up with one?

Opioid drugs themselves illustrate how challenging it is to develop effective painkillers without serious side effects. Opioids work by acting on so-called mu-opioid receptors, which are concentrated in regions of the brain that control our perception of pain. But mu-opioid receptors are also present elsewhere in the brain and the body, which is why opioids produce such serious side effects. In addition to dulling our perception of pain, opioids stimulate receptors in the brain's "reward" regions to produce the buzz, in the gut to produce constipation, and in the brain stem to depress breathing—which is what kills people when they overdose. An ideal opioid would avoid side effects by targeting only the correct set of mu receptors, but that's no easy task—once in your bloodstream, a drug is carried throughout your body and can easily reach the wrong targets. All existing painkillers have this problem.

Because of the challenging scientific and market conditions for new painkillers, drug companies have cut their investment in neurobiology and pain research over the past decade. Public investment hasn't been impressive either: Pain research represents less than 3 percent of the budget of the National Institutes of Health. But as the opioid crisis takes its toll, the stakes are changing. There is now a much stronger incentive to invest in the science of pain and the development of new painkillers. According to Nora Volkow, the director of the National Institute for Drug Abuse, and her colleague Phil Skolnick: "An obvious need for improved treatments, especially in chronic pain conditions, appears to create an ideal environment to foster the development of novel pain therapies. Nevertheless, efforts in this direction have lagged far behind the need."

But it takes years to develop new drugs, even with robust investment. As a more immediate response to the opioid crisis, pharmaceutical companies have come up with so-called abuse-deterrent formulations of opioids. These are expensive new versions of existing drugs that are designed to foil people who tamper with opioid pills for a better high. For example, abuse-deterrent OxyContin turns into a gel if you try to dissolve it, which makes it impossible to inject. But you don't have to inject OxyContin to abuse it—you can simply swallow a higher dose of pills and still become addicted. As Yale School of Medicine physicians William Becker and David Fiellin note this month in the New England Journal of Medicine, labeling these drugs as "abuse-deterrent" may mislead the physicians who prescribe them. "Abuse-deterrent formulations don't prevent patients from taking higher doses than prescribed, which is the most common way opioids are misused," they write. "Yet one survey showed that nearly half of primary care physicians think abuse-deterrent formulations are less addictive than standard formulations."

Abuse-deterrent opioids aren't without their merits, but they don't solve the underlying problem, which is that we lack safe, non-addictive drugs to treat our society's massive burden of chronic pain. "We cannot hope to prevent opioid misuse and overdose without addressing the treatment needs of people with moderate-to-severe chronic pain," write Volkow and National Institutes of Health Director Francis Collins in a report last month. But this will require a renewed public and private investment in the science of pain, something in which the Trump administration, with its massive proposed cuts to medical research, shows little interest.

In spite of the challenging science, there are some promising leads to pursue. Drugs that target the molecules involved in the cannabinoid system, which responds to the active ingredients in marijuana, show promise in mouse studies. Another possible drug target is the gene Nav1.7. Some people who carry mutations in this gene perceive no pain, and a study published this year found that a component of tarantula venom targets Nav1.7 and relieves pain in mice. There are also ongoing early stage clinical trials of new drugs that might pull off the trick of only activating mu-opioid receptors to produce pain relief, without the addictive and respiratory suppressive effects of current opioids.

Most pain drugs on the market today are, in one way or another, based on pain-relieving substances that humans have been using for millennia. The ancient Greeks used both opium and salicylate (which is chemically related to aspirin). With science, we've improved these basic painkillers over the past two centuries. With enough public and private investment, there is no reason why this progress can't continue, or even lead to fundamentally new ways of treating pain. "As we have seen repeatedly in the history of medicine, science is one of the strongest allies in resolving public health crises," Volkow and Collins write in their report. "Ending the opioid epidemic will not be any different."

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