James Hackworth discusses rethinking risk, reward and what pain scores don’t tell developers about a new analgesic.
For James Hackworth, PhD, Cebranopadol Development Lead at Adneuris Therapeutics, a wholly owned subsidiary of Tris Pharma, the science behind pain treatment intersects with his own experience of it.
James entered the pharmaceutical industry after earning a PhD in physics and working in consulting. His interest in pain grew partly from seeing chronic pain affect members of his family.
One relative, he recalled, was prescribed opioids after a serious car accident, later developed an addiction and eventually died of an overdose.
“I’ve sort of seen both sides of the need,” James said.
It is this tension between treating pain adequately and limiting treatment-related risks that drives much of his thinking about analgesic development.
Cebranopadol Development Lead
Adneuris Therapeutics, a wholly owned
subsidiary of Tris Pharma
In an interview with Xtalks Clinical Edge, James discussed the nuances of acute pain, how researchers are investigating different pain pathways and why pain scores alone are not enough to determine if a potential analgesic is clinically useful.
When Pain Relief and Treatment Risk Collide
When someone is concerned about opioid use, avoiding pain medication altogether can seem like the safest choice. But James argued that severe pain carries risks of its own.
“The biggest thing is people think of pain as only a comfort issue,” he said.
Neuroplasticity is the nervous system’s ability to change in response to repeated signals. It is one of the reasons poorly controlled severe pain deserves attention.
In some cases, pain signaling can persist even after the original injury has healed, a kind of phantom-limb effect for pain itself.
Existing treatment options, however, can leave clinicians with difficult choices. James said nonsteroidal anti-inflammatory drugs (NSAIDs), acetaminophen and other non-opioid analgesics can be effective, particularly when used together, but often carry an efficacy ceiling that leaves moderate or severe pain undertreated.
While opioids can close that gap, they also bring respiratory depression, misuse and physical dependence.
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It is a trade-off, and one that shapes what developers need to show from a new pain therapy. It’s not enough, James said, for a new drug to simply match what’s already on the market.
“It has to be safer. It has to be less addictive. It has to have advantages on the safety side or else, frankly, it really wouldn’t be interesting,” he said.
But clinicians are not immune to bias. James noted that clinicians can form assumptions about who is likely to misuse a medication and who isn’t, assumptions that aren’t actually predictive.
James noted that some surgeons prescribe opioids for only a short window and may never see the dependence that develops later, by which time a patient has moved on to another provider.
Dependence is unpredictable and is something James has thought about outside the clinic, too. He described comparing notes with a colleague about their very different responses to the same everyday habit: caffeine.
“I’ll start feeling withdrawal. I get a headache. I feel tired,” James said. His colleague, who drinks more caffeine than he does, reported barely noticing when he stops.
“Why does it affect me one way and him in a different way? Nobody knows. It just is,” James said.
Susceptibility to physical dependence and withdrawal can vary considerably from person to person.
Looking Beyond Conventional Opioid Pharmacology
Current pain research can be grouped into several broad approaches.
One approach is to work with established pain pathways while changing their safety profile. His own work includes cebranopadol, an investigational compound that acts on both opioid receptors and the nociceptin/orphanin FQ peptide receptor, or NOP receptor.
— James Hackworth, PhD, Cebranopadol Development Lead, Adneuris Therapeutics, a wholly owned subsidiary of Tris Pharma
The development hypothesis is that activating the NOP system alongside opioid pathways could preserve analgesia, extend it into other types of pain and reduce some of the risks typically associated with conventional opioid activity.
Other developers are improving the safety of a mechanism that already exists. James brought up South Rampart Pharma, an earlier-stage company working on a molecule related to acetaminophen. Conventional acetaminophen’s dose is capped because of the risk of liver toxicity during metabolism, but James said South Rampart’s compound is metabolized differently, potentially allowing more efficacy from that pathway without the same liver toxicity.
Another arm of research looks at the peripheral nervous system, aiming to interrupt pain signals before they ever reach the brain. James pointed to Journavx (suzetrigine), approved by the FDA last year, which operates through a new mechanism built on a pathway researchers had tried and failed to target for years. Other companies are also pursuing similar peripheral targets.
Some earlier-stage research is asking a more fundamental question: whether the underlying biology of chronic pain itself can be changed. These approaches are investigating whether the same principles of neuroplasticity that let pain become “stuck” in the nervous system could also be used to reverse it. Though this is some of the most interesting work in the field, he said, it remains early and less proven.
How Addiction Research Shaped a New Analgesic Hypothesis
Cebranopadol’s development has roots in addiction research.
Researchers were examining how the NOP pathway interacts with dopamine signaling and substance-use behavior.
“What it showed in the addiction space is if you stimulate the NOP receptor at the same time as you give an animal the ability to abuse an opioid, a stimulant like cocaine or amphetamine or even alcohol, it can completely change that behavior and attenuate it and make them not want to do that,” James said.
He added that researchers linked the effect to blocking dopamine release in the brain’s pleasure centers. James described this dopamine release and the resulting euphoria as one reason people may repeatedly return to drugs such as cocaine or heroin.
That work helped shape the hypothesis that if one drug stimulated both the opioid and NOP systems, the NOP activity might act as a built-in brake on the abuse potential that opioids carry alone.
Along the way, James said, researchers have come to appreciate that the relationship between the two systems runs deeper than originally understood.
Why Acute Pain Trials Use Different Surgical Models
Patients experience pain differently, and different injuries involve different types of tissue.
Bunionectomy and abdominoplasty are two well-established postoperative models used in acute pain research. Researchers have considerable experience with both procedures, James said, and the surgeries provide relatively standardized settings in which to compare treatments, reducing the risk of false positives or false negatives.
They also represent different kinds of postoperative pain. James explained that bunionectomy is predominantly hard-tissue or bony pain, while abdominoplasty largely represents soft-tissue pain involving muscle, skin and fat. Studying both gives researchers a way to see how an investigational analgesic performs across these different settings, since not every drug affects hard- and soft-tissue pain equally.
In the real world, acute pain often involves both categories at once. A car accident, for instance, might cause broken bones alongside significant soft-tissue damage. Used together, James said, the two models effectively become a proxy for these much larger categories of pain than the surgeries themselves represent. He added that this approach has proven predictive of how a drug performs in other surgical and non-surgical settings.
— James Hackworth, PhD, Cebranopadol Development Lead, Adneuris Therapeutics, a wholly owned subsidiary of Tris Pharma
Pain Scores Are Only Part of the Trial Result
So how large does a change in a pain score need to be before it actually matters to patients?
There is no single numerical answer, according to James. Clinical relevance depends on the therapy’s overall benefit-risk profile.
“These drugs aren’t used in isolation. They’re studied in clinical trials in isolation,” James said. “But in the real world, they use three or four or five drugs after surgery. And so you’re using them together.”
That means even a drug with modest efficacy could still add useful pain relief if it works through a different pathway. On the other hand, a drug with substantial side effects would need to offer enough benefit to justify those risks.
“I think it’s more of a risk benefit than an absolute, this is meaningful and that’s not meaningful,” James said.
Individual responses vary considerably. James recalled that in some trials, a small number of placebo-treated participants required no rescue medication at all, while other participants experienced substantial pain even after receiving analgesics.
In acute pain trials, participants can take additional medication, called rescue medication, if the study drug isn’t enough. James explained that trial analyses account for this, so the investigational drug doesn’t get credit for relief the rescue medication actually provided. But how often patients need rescue medication, especially an opioid, is also looked at as a result in its own right.
— James Hackworth, PhD, Cebranopadol Development Lead, Adneuris Therapeutics, a wholly owned subsidiary of Tris Pharma
“If you say you’re developing a new drug and you say, ‘Okay, well, it kind of works,’ but then 80% of the patients had to take an opioid on top of it, well, okay, we still have this problem we’re dealing with,” James said.
Patient function matters too, though James noted that short trials like bunionectomy and abdominoplasty don’t capture it well. Broader studies in other surgical and non-surgical settings, he said, can show more about how a drug performs in real-world use.
Failing Faster: Why Pain Research Needs Better Early-Stage Tools
One of the biggest opportunities in pain drug development is in early clinical development.
Pain research has faced very high failure rates in this stage, James said, partly because findings from animal studies don’t always translate cleanly into humans and partly because tolerability can limit the doses researchers are able to test in people.
“We need better tools in order to figure out how to select molecules in an early stage,” James said.
Experimental pain models can be tested in healthy volunteers early in clinical development using controlled, induced pain to check whether a mechanism is behaving as expected before moving into larger, more expensive patient trials.
“Those ideas have been around for awhile, but I think there’s been actual real progress to validating those approaches now,” James said.
If those tools prove reliable, they could help developers decide which molecules to stop and which are worth pushing into a full clinical program.
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