There’s So Much We Still Don’t Know About Pain

Opioids remain the most effective drugs available for treating many kinds of pain — largely because we still don’t truly understand the science of pain.

Illustration by Sara Andreasson for HuffPost

This story is part of Pain in America, a nine-part series looking at some of the underlying causes of the opioid addiction crisis and how we treat pain.

The story we’ve been telling about the opioid overdose crisis in the United States, says civil rights lawyer Kate Nicholson, is a tidy narrative: Big Pharma pushed potent narcotic painkillers, doctors overprescribed them, people got addicted, and many ended up dead in the street.

“It’s a lovely story with an evil villain and duped doctors and innocent victims,” she says. But the truth isn’t so simple.

Nicholson lived with chronic pain for a decade and a half after suffering nerve damage from surgery. It didn’t happen right away, but came on suddenly a year later. She was 30, sitting in her Washington, D.C., office, when a searing pain shot through her back. The pain spread, and it stayed. She spent three years in agony, unable to sit, barely able to stand, using a walker to get around. She was often bedridden.

She resisted her doctors’ suggestions to take prescription narcotics. It was the late 1990s. OxyContin had recently come on the market, prescriptions were on the rise, and Nicholson worried about the risk of addiction. But after exhausting all other options, she started on methadone and oxycodone. They worked.

Seventeen years later, when the opioid overdose crisis captured the nation’s attention, she found herself fighting to get the pills she needed to function.

Kate Nicholson, seen at her home in Boulder, Colorado, is a civil rights attorney and pain patient advocate who lived with chronic pain for nearly two decades after suffering nerve damage from surgery.
Kate Nicholson, seen at her home in Boulder, Colorado, is a civil rights attorney and pain patient advocate who lived with chronic pain for nearly two decades after suffering nerve damage from surgery.
Rachel Woolf for HuffPost

Since 2016, two-thirds of states have passed laws that limit how much of an opioid painkiller doctors can prescribe, and how many days they can prescribe them for. Hospitals, insurers and pharmacy chains imposed maximum dosage and duration rules, and drug enforcement has targeted doctors deemed as overprescribers, without a clear definition of what that actually constitutes. Doctors, often wary of oversight, are swiftly reining in prescriptions.

“Suddenly everyone wanted to fix this problem,” says Nicholson. “There was just this rush of regulation and simplistic, one-size-fits-all approaches to a condition that’s so broad and so varied.”

That approach has left many people who rely on opioids for pain management, and the people who treat them, with fewer options. It also ignores what drove so much prescribing in the first place, and why opioids are so widely used: They are the most effective drugs currently available for treating many kinds of pain. And the reason that’s true is because we still don’t truly understand the science of pain.

The Enduring Allure Of Opioids

People have treated pain with opioids for millennia. Scholars say 8,000-year-old Sumerian clay tablets may have been the first prescriptions for opium, from poppies. Its use has been documented all over the world, from ancient Greece to China and the New World.

Opium was known for creating a feeling of euphoria, which made it an attractive sedative and pain reliever. In the early 1800s, a German scientist first isolated the active ingredient in opium to make morphine. By the turn of the century, addiction to morphine and opium reached epidemic levels in the United States. Meanwhile, back in Germany, the new pharmaceutical arm of the chemical company Bayer was developing an opioid drug that was believed to be more potent than morphine and less addictive. They named it heroin.

Today there are around two dozen forms of opioid analgesics, also known as narcotic analgesics, including morphine, oxycodone (used in brand-name medications such as OxyContin, Percodan and Percocet), hydrocodone (Vicodin) and hydromorphone (Dilaudid).

The wide-ranging actions of opioids in the body are what make them so effective, so alluring and so dangerous. Opioids work as analgesics by binding to particular types of receptors in certain nerve cells in the spinal cord and brain, interrupting pain signals. They also activate circuits in parts of the brain involved in pleasure and reward, which both elicits a high and gives them their addictive potential. Acting on parts of the brain stem and other areas involved in respiration, they can slow breathing, which is often the cause of fatal overdoses.

Opioids, including prescription painkillers, were involved in 46,802 overdose deaths in 2018 — more than two-thirds of all fatal drug overdoses in the U.S. that year. But most people who die from an overdose involving an opioid didn’t get the drug from a doctor. Opioid prescription rates fell 28% from their peak in 2012 to 2017 amid a push for policies to reduce use and doctors tapering patients off long-term regimens. Opioid overdose deaths more than doubled over that same period.

The increase in deaths was propelled in large part by the proliferation of cheap, powerful, illegally produced synthetic opioids like fentanyl. And recent studies have found that cutting off prescriptions to opioids is one reason some people suffering with pain have sought to self-medicate with illicit drugs, putting them in danger of overdose. Fentanyl deaths doubled every year from 2013 to 2016, when it overtook heroin as the top drug involved in fatal overdoses.

With all the risks that come with opioids, why do we keep using them? Because they work, and because science hasn’t found anything nearly as effective for so many different kinds of pain.

Why Pain Is So Hard To Treat

“We use ‘pain’ as one word, but I think it reflects a panoply of different disorders,” says David Julius, chair of physiology at the University of California, San Francisco, School of Medicine, who has spent decades trying to understand how humans perceive pain.

Pain can be recovery from a broken ankle or a pulled wisdom tooth. It can be migraines, or backaches, or the burning of chemotherapy-induced neuropathy, or debilitating sickle cell episodes. Pain can be in muscles, bones, nerves.

Pain has long been treated with a very limited arsenal of drugs that don’t precisely distinguish between one type of pain and another. The biggest reason is that scientists don’t yet understand all the mechanisms that cause pain, Julius says. “You got to understand how things work before you can fix them. Otherwise you’re taking potshots in the dark.”

The path of pain starts with sensory neurons that activate in response to a stimulus. From there, the neural signal travels to the spinal cord and up into the brain. It’s a chain that gets more complicated the further up you go, and there are mysteries at every step that scientists are still trying to unravel.

Julius’ work focuses on the first step: what is happening on a cellular level when you feel pain. In the late 1990s, he figured out that the reason we get a burning sensation from chili peppers — or, more specifically, the capsaicin that gives them their kick — is that they activate receptors in nerve cells that also respond to painfully high heat. Julius’ lab also discovered the so-called wasabi receptor, which responds to both its pungent namesake and inflammation in the body.

Researchers have since discovered dozens of these markers, but there could be hundreds more, each with the potential to help develop more targeted pain medications.

And those are just the receptors involved in how sensory nerves at the periphery respond when you sprain your ankle or touch a hot stove. That kind of pain is protective; it’s what tells you to stop running or move your hand away. We understand even less about how or why pain can persist for months or years after injured tissue has healed. This chronic pain can limit a person’s ability to function, to work, to take care of their family. And because the neural pathways in the brain that process pain overlap with ones associated with mood and emotion, it can trigger anxiety and depression, which can in turn make chronic pain feel even worse.

“Those are the patients that are the most difficult to treat and the ones that really need to have new medicines discovered,” says Frank Porreca, a professor of pharmacology and anesthesiology at the University of Arizona who studies pain and the effects of opioids on the brain.

For patients suffering acute and cancer pain, opioids have long been among “our most important drugs,” he says. A few decades ago, doctors started extending the same treatments to people with chronic pain, fueling the rise in opioid prescriptions. It’s a tricky proposition. While some people may get relief from the medications, there is no good data showing that they’re safe and effective when used long term.

What is known, however, is that the longer a person is on opioids, the more likely they are to become addicted. Whether the benefits of opioids outweigh the risks for such patients is a murky question for doctors to answer.

“The choices physicians can make are limited,” Porreca says.

The Twisted Roots Of A Crisis

In many ways, the opioid overdose epidemic is a story of good intentions gone wrong. There are bad guys, to be sure. Unscrupulous pharma execs spouting unfounded claims and paying doctors to push their drugs. Unethical doctors running pill mills and flooding the streets with prescription narcotics. Dealers distributing lethally strong fentanyl. But broad assumptions that paint opioids as bad and prescribers as shills obscure legitimate efforts to ease people’s suffering and ignore how hard that is to do.

“There’s a constant blurring of Purdue products and opioids in general, including cheap generic oral morphine, which costs pennies and from which no one is making a fortune,” laments Daniel Wolfe, who directs harm reduction programming at Open Society Foundations. “We work in so many countries where there is no pain relief whatsoever, including oral morphine. A terrible thing about the Purdue scandal is that it casts a pall over an entire category of medications.”

The explosion in opioid prescriptions and the overdose epidemic that resulted came from a confluence of interwoven agendas, some more noble than others.

In the 1980s and ’90s, pain management specialists felt that many people were being undertreated for pain. “Unlike ‘vital signs,’ pain isn’t displayed in a prominent place on the chart or at the bedside or nursing station,” wrote Mitchell Max, then president of the American Pain Society, in a 1990 editorial in the Annals of Internal Medicine.

The APS began to encourage doctors and nurses to routinely monitor pain like they would the four vital signs — blood pressure, pulse, breathing rate and temperature — and not to be afraid to treat with opioids as well as nonopioid analgesics, a well established combination for patients with cancer or acute pain following injury or surgery. It also suggested that hospitals hold formal reviews to ensure that patients were satisfied with how well their doctors addressed their pain.

Opioid prescriptions were already on the rise at that point. Doctors were giving them to patients with chronic, noncancer pain, propelled in part by the belief that they came with a low risk of addiction. That belief, which would persist for decades, was based largely on badly misinterpreted information, most notably a scant, one-paragraph letter published in the New England Journal of Medicine in 1980 reporting less than 1% addiction rates among patients with no history of addiction being treated with narcotic painkillers while hospitalized.

“The acceleration in the use of opioids for chronic pain that happened in the ’80s and ’90s was not based on strong science,” says Rosemary Polomano, professor of pain practice at the University of Pennsylvania School of Nursing.

By the early 2000s, the notion of pain as “the fifth vital sign” caught on, as influential organizations like the Veterans Health Administration and The Joint Commission, which certifies and writes standards for health care practices, started using it. The Joint Commission’s standards encouraged hospitals to have patients rate their pain on a 10-point scale to give clinicians quantitative information on which to base treatment decisions.

But unlike blood pressure or temperature, pain is not an objective measure. “You can ask a patient, ‘How much pain do you have?’” says Porreca. “But there’s no blood test. You can’t measure pain.”

Because pain is subjective (and subject to mood), such ratings aren’t totally reliable measurements. Still, doctors used the ratings to routinely assess their patients’ pain, and hospitals used them to routinely assess their doctors’ performances in pursuit of better marks for patient satisfaction.

Worries started to grow in the medical community that the edict to treat pain more vigorously would lead to overuse of opioids. Concerned its message was being taken more literally and applied more broadly than intended, The Joint Commission removed references to the fifth vital sign from its standards within three years, but the notion had already taken hold. “Rather than seeing the phrase as an analogy to draw attention to the need for improved assessment ... some organizations interpreted this to mean that pain needed to be assessed every time vital signs were taken,” one commission executive explained recently in a JAMA op-ed. “There were also signs that some clinicians had become overzealous in treating pain.”

The increased focus on treating pain came at a perfect time for Purdue, which had begun aggressively marketing its new long-acting opioid, OxyContin, in 1996. The company’s army of sales reps claimed it was effective for many types of non-cancer-related pain with a lower likelihood of abuse and addiction than similar drugs already on the market. Sales of OxyContin ballooned to $1.5 billion by 2002. Five years later, Purdue pleaded guilty to intentionally misbranding the drug as less addictive. The company paid $600 million in fines.

Opioid sales overall had quadrupled between 1999 and 2010, as did the number of overdose deaths involving prescription opioids.

The Pendulum Swings Back

Knee-jerk adherence to new standards inflated the use of opioid pain medicines that helped create the overdose crisis. Current attempts to solve the problem are repeating old mistakes in reverse. New regulations focus on limiting doctors’ ability to prescribe opioids, which can result in undertreatment of pain, the very thing clinicians were trying to avoid 30 years ago.

In 2016, the Centers for Disease Control and Prevention released opioid prescribing guidelines to help primary care doctors safely and effectively treat patients with chronic pain. The guidelines included a dozen detailed recommendations for assessing a patient’s needs and appropriate interventions to try.

Practitioners, hospitals, insurers and state governments seized on the CDC guidelines, often interpreting dosage recommendations as hard and fast limits for prescribing, and working them into practice standards, reimbursement strategies and laws. That was not, the authors clarified last year, the agency’s intention.

While these efforts were “laudable,” they wrote, “unfortunately, some policies and practices purportedly derived from the guideline have in fact been inconsistent with, and often go beyond, its recommendations.”

Doctors, fearing that prescribing above those thresholds could result in malpractice lawsuits, having their medical licenses revoked, or arrest, began reducing or stopping their patients’ opioid prescriptions, even for those who’d had long-term success on the medications and were not addicted.

“Now the pendulum is swinging a little too far away from opioids for any circumstances, and that’s just not correct,” says Porreca. “There are patients that should be treated with opioids for their pain. That should not be overlooked.”

Kate Nicholson had tried everything her doctors could think of before she started taking opioid medications for her chronic pain: steroids, nonsteroidal anti-inflammatories, nerve blocks, infusions, catheters in her spine and surgery. Nothing helped.

“Once all of those things had been tried,” Nicholson tells HuffPost, “my doctors sat me down and said, ‘We are going to take a different approach. We have put you through painful procedure after painful procedure. We have an oath to do no harm — we want to put you on opioids.’”

She started a regimen of daily methadone, plus oxycodone for breakthrough pain, which she stayed on for 17 years.

The drugs allowed her to get back to work, though she was still limited in her ability to sit, stand or walk. She once argued a federal case while reclining in a folding lawn chair.

In 2014, she moved from Washington, D.C., to Boulder, Colorado, for fresh air and a slower pace. There, she came face to face with the problem of doctors afraid to prescribe opioid pain medications. A well respected local physician had been arrested in a Drug Enforcement Administration sting for allegedly overprescribing oxycodone. The medical community was shaken.

“I was already going down [in dosage] on the opioids,” Nicholson recalls. “I went to the doctor and she said, ‘I won’t prescribe opioids to you anymore and you won’t find anyone in town who will either.’ And in fact, I couldn’t find anyone.”

She flew back to D.C. and got her doctors there to put her on a plan to taper off the medications safely. Thanks to the careful long-term care of her treatment team at Johns Hopkins and new surgical techniques — accessible because she had good health insurance and the money to buy plane tickets — her pain ultimately subsided.

Most don’t have the resources Nicholson did. That’s why, for the last few years, she has been working as an advocate, trying to ensure that people who need opioids to function don’t lose their medications in the response to the overdose crisis.

Some states have imposed limits on how much of an opioid medication will be covered under Medicaid, putting low-income Americans with chronic pain at risk of losing their medication. Last year, Oregon’s health authority was forced to walk back a controversially stringent policy requiring doctors to taper their Medicaid patients off opioids. The federal agency in charge of Medicare and Medicaid was also pressured to change a proposal that would have put a lock on prescriptions of 90 morphine milligram equivalents or above.

“Marketing and overprescribing played a role in creating the crisis, but now that you have created tens of thousands of people who need this medication, you can’t just turn off the tap and say, ‘Sorry we made a mistake,’ and think people won’t suffer intensely or turn to illegal sources,” says Wolfe. “‘Do no harm’ seems to have been lost from the equation.”

The Quest For Better Science

While the role opioids should play in pain management is still in question, it’s become clear that doctors need better science, smarter standards and new, less-addictive treatment options.

There’s a strong effort to find alternatives. The National Institutes of Health’s Helping to End Addiction Long-term program, or HEAL, committed $945 million last year to 400 research projects aimed at reducing and treating opioid use disorder and improving pain management, particularly for chronic pain. That includes studies to identify the proper use of opioids for particular conditions and patient populations, as well as the work of researchers such as David Julius at UCSF to understand the underlying mechanisms of pain.

But drug development takes time. In the meantime, policies — at hospitals, insurers, and at the state and federal levels — need to incentivize the use of alternative therapies, and treatments that employ multiple classes of pain medication to reduce reliance on opioid drugs. There are also efforts to improve how prescribing guidelines are written to help doctors — especially general practitioners, as well as pharmacists and nurse practitioners — make better-informed decisions based on the best available science when treating people with a range of medical needs and risk factors for addiction or substance use disorder.

“We don’t have all these other ways of treating pain that are accessible and evidence based,” said Nicholson. “We made a lot of mistakes that we need to correct. But we need to do it well.”

Need help with substance use disorder or mental health issues? In the U.S., call 800-662-HELP (4357) for the SAMHSA National Helpline.

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