As opioid-related deaths skyrocket across the U.S., momentum to combat the epidemic has been mounting in Washington. But the crisis has also highlighted a glaring problem that no amount of politics or policymaking will solve soon: The lack of non-addictive pain medicines.
“What is disappointing over the last half-century is that we haven’t really created any new, more effective categories of pain medicines,” says Jianren Mao, chief of pain medicine at Massachusetts General Hospital and director of the MGH Center for Translational Pain Research. New pain drugs have all belonged to existing classes such as opioids and non-steroidal anti-inflammatory drugs.
The need for new drugs is urgent. Drug overdose is now the leading cause of death for Americans under 50, most of it attributable to opioids. More than 64,000 people in the U.S. died of drug overdoses last year, a number that has quadrupled since 1999. According to the Substance Abuse and Mental Health Services Administration, more than 11 million people misused prescription opioids in 2016.
Congress has held hearings. The nation’s health agencies have unveiled new actions. After months of promises, President Trump declared a national public health emergency. The latest development on the political front—today’s final report from President Trump’s opioid crisis commission—has a few recommendations that address R&D issues such as the dearth of non-addictive alternatives for pain treatment. But many of the report’s 56 recommendations focus on more immediate actions such as boosting access to addiction treatment and beefing up law enforcement to reduce illicit opioids. Chaired by New Jersey governor Chris Christie, the commission has met with doctors, patients, insurers, biopharma executives and others since it was first formed in March.
The opioid epidemic is complex, but it’s clear doctors need better options for alleviating pain, particularly chronic pain. This kind of pain can linger for years or even a lifetime, affects some 100 million Americans, and has been linked to depression, lost productivity and a host of other problems.
But for a variety of reasons, development of new non-addictive treatments has lagged behind drug development in other therapeutic areas. Mao says the medical field has made progress in the treatment of acute and post-operative pain, as well as pain from migraine headaches, but when it comes to chronic pain, “we are truly deficient in better treatment options.”
Why the meager pipeline? There are dozens of possible drug targets, says Mao, and researchers have a pretty good understanding of the biological underpinnings of pain.
But progress in the lab isn’t carrying over to the clinic because the animal models used in early studies don’t fully recreate pain in humans. We experience pain subjectively, says Mao. Some injured people report distressing, long-lasting pain, while others with the same injury return to work in just a few days.
This difference in pain perception is hard to mimic in animals. A potential drug that appears to reduce signs of pain in animals may have very different effects in people, as Sharon Hertz, director of FDA’s anesthesia, analgesia and addiction products division, explained in a presentation last year.
Once a drug reaches humans in clinical trials, the lack of objective measures—participants self-report pain using numerical scales— also causes problems. When patients report their own outcomes, the placebo effect becomes an issue. Subjects in a trial who aren’t getting the drug can often still report pain relief, and this can make it difficult to see a statistically significant effect of the drug in people who actually are getting the drug.
To deal with the placebo effect, drug sponsors need to run larger, costlier trials, with up to 600 patients, says Steve Doberstein, senior vice president and chief scientific officer of San Francisco-based Nektar Therapeutics (NASDAQ: NKTR). (Nektar plans to file for FDA approval next year for its opioid, which has been chemically modified to enter the brain more slowly and not produce the “high” of other opioids.)
James Campbell, president and chief scientific officer of Centrexion Therapeutics, says his Boston-based company, which is devoted solely to finding new treatments for chronic pain, has been thinking a lot about better ways to design clinical trials. “There is plenty of room for innovation on how to do clinical trials” for pain, says Campbell. (Centrexion will soon be launching a phase 3 trial of its non-opioid compound for osteoarthritis pain, and has five other non-opioids in its pipeline.) Campbell says his team is looking at ways to better train both clinical investigators and trial participants to lessen the placebo effect and the variability in pain reports from patients.
Campbell and other biotech executives spoke before the commission in Washington in September. One common theme was the lack of coverage of non-opioids and drugs for addiction treatment from insurance companies. Campbell cited a New York Times report about how opioids have been easier to obtain than safer but more expensive alternatives, thanks to insurance plan policies.
David Stack, CEO and chairman of Pacira Pharmaceuticals, told the Commission there’s little incentive for hospitals to use non-opioids for post-surgical pain (such as an injectable product from Pacira) because of the way hospitals are reimbursed by Medicare.
Indeed, today’s commission report urges the Centers for Medicare and Medicaid Services to review policies that discourage the use of non-opioid treatments for pain. “We should incentivize insurers and the government to pay for non-opioid treatments for pain beginning right in the operating room and at every treatment step along the way,” wrote Governor Christie in a letter to President Trump today.
Insurance companies and pharmacy benefit managers have responded in recent months, announcing how they are working to limit prescriptions and reduce use of opioids. A UnitedHealthcare spokesman told the New York Times: “All opioids are addictive, which is why we work with care providers and members to promote non-opioid treatment options for people suffering from chronic pain,” he said.
With all these challenges, it’s no surprise that the pain field is seen as a risky area of drug development. Campbell told the commission: “A substantial barrier to the development of novel pain treatments is the widespread, though we believe largely inaccurate, perception that this kind of drug development has a higher risk of failure than is seen in other therapeutic areas,” making it hard to attract investment to the pain drug area. He went on to recommend ways that the FDA could provide more incentives to developers of non-opioid drugs that would make the field more attractive to investors.
Tackling the Challenges
Last week, FDA commissioner Scott Gottlieb told Congress that the agency wants to pull the levers it has at its disposal to promote the development of safer pain treatments, such as expediting the review of such products.
The National Institutes of Health has partnered with more than 30 drug companies and academic centers to find ways to accelerate the development of new non-addictive pain medicines. They are putting together a plan to build a clinical trials network with cohorts of pain patients and work toward better, more objective measures of pain.
But as NIH director Francis Collins said to the commission in September, this public-private partnership is going to need funding to really get off the ground.
As observers immediately noted after the president’s declaration last week, his designation of “public health emergency” does not provide additional funding for these sorts of initiatives. The commission’s report today said the NIH should receive new money for research but stopped short of recommending funding levels.
Even if safer pain medicines come to market, Mao, who treats pain patients at Mass General, says new drugs won’t completely solve the pain problem. It’s going to take both medical and non-medical solutions, including exercise, acupuncture and other therapies. “We need to educate the nation and set the right expectations,” says Mao. “We are talking about the management of pain, not the eradication of pain.”