Should Rx Opioids Be Limited for Cancer Patients?

By Pat Anson, PNN Editor

At a time when many chronic and acute pain patients are losing access to opioid medication, patients suffering from cancer pain are treated differently. They’re usually exempt from opioid guidelines that typically focus on limiting prescriptions for “noncancer pain.”

But some oncologists are starting to question whether opioids should be routinely prescribed to cancer patients.

“As an oncologist, I cannot help but reflect on that qualifier. It suggests that a cancer diagnosis gives us permission to prescribe opioids with impunity. Patients with cancer can become addicted, like anyone else. Yet oncologists use these potent, seductive drugs freely, perhaps without sufficient regard for the risk of dependence and abuse,” writes Alison Loren, MD, in an op/ed published in The New England Journal of Medicine.

“Treating patients who are terminally ill from cancer is an important indication for these drugs. But what about patients with cancer who aren’t dying, the ones we hope to cure? Woven into our language about the opioid epidemic is an implication that oncologists can hand out opioids as if there were no tomorrow. But for many people with cancer, there is now indeed a tomorrow.”

Loren, who is a professor at the Perelman School of Medicine at the University of Pennsylvania, says many patients whose cancer was once thought incurable are living for a decade or longer. Thanks to advances in cancer treatment, there are more than 15 million cancer survivors in U.S. and their ranks are growing

“With this progress comes new challenges. Especially poignant — albeit rare — is the one I face when I see a patient who is cancer-free but addicted to medications I’ve prescribed,” wrote Loren. “I am responsible for this predicament, and it feels monstrously cruel — second only to allowing the dependence to continue. Sometimes, like those with ‘noncancer pain,’ our patients veer into abuse.”

bigstock-Too-Many-Pills-272768.jpg

A new study by researchers at the University of Colorado School of Medicine found signs of opioid abuse in a small percentage of cancer patients. Out of 811 patients given opioids after treatment for oral or oropharynx (neck) cancer, 68 patients (7%) were still using opioids six months later.

"You shouldn't need opioids at the six-month point," says Jessica McDermott, MD, an investigator at the CU Cancer Center. “We felt like (opioid misuse) was a long term problem for some of our head and neck cancer patients, but didn’t know how much of problem.”

McDermott doesn’t advocate taking opioids away from cancer patients, but says doctors should know which patients are more at risk of opioid misuse, such as those having a previous opioid prescription or a history of smoking and alcohol use.

"If a patient needed opioids for pain, I wouldn't keep them away, but especially if they have risk factors, I might counsel them more about the risks of addiction and misuse, and keep an eye on it," McDermott says.

Loren would take opioids away from a cancer patient at risk of misuse. She shared the story of a leukemia patient with a long history of substance abuse who was found dead in her hospital bed.

“Her leukemia was in remission. The possibility that she may have overdosed haunts me,” Loren wrote. “Oncologists are accustomed to giving opioids, but we must also be comfortable taking them away, and sometimes giving them in limited doses or not at all.”

Is Pain a Self-Fulfilling Prophecy?

By Pat Anson, PNN Editor

Getting out of bed, taking a shower, doing the dishes and other simple chores can be painful experiences for someone with intractable chronic pain. But some of that pain may be self-fulfilling: Getting out of bed hurts because you expect it to.

That's the theory behind a new brain imaging study published in the journal Nature Human Behaviour, which found that false expectations about pain can persist even when reality demonstrates otherwise.

"We discovered that there is a positive feedback loop between expectation and pain," said senior author Tor Wager, PhD, a professor of psychology and neuroscience at the University of Colorado Boulder.

"The more pain you expect, the stronger your brain responds to the pain. The stronger your brain responds to the pain, the more you expect."

Wager and his colleagues recruited 34 people for a heat test to see if the expectation of pain can cause changes in neural mechanisms of the brain.

bigstock-Insomnia-A-man-tries-to-fall--27249281.jpg

Participants were taught to associate one symbol with low heat and another with painful heat. Then, the subjects were placed in a functional magnetic resonance imaging (fMRI) machine, which measures blood flow in the brain as a proxy for neural activity.

For 60 minutes, subjects were shown the low or high pain cues (the symbols “Low” and “High” or the letters L and W), and then asked to rate how much acute pain they experienced as heat was applied to their forearms or legs. Unbeknownst to the participants, heat intensity was not actually related to the preceding cue.

The study found that when subjects expected more heat, brain regions involved in threat and fear were more active as they waited for the heat to be applied. Regions involved in the generation of pain were also more active when they received the stimulus.

The result? Participants reported more pain with high-pain cues, regardless of how much heat they actually got.

"This suggests that expectations had a rather deep effect, influencing how the brain processes pain," said lead author Marieke Jepma, PhD, a researcher in Wager's lab who is now a researcher at Leiden University in the Netherlands.

Many subjects also demonstrated a high degree of confirmation bias -- a tendency to learn from things that reinforced their beliefs, while discounting those that didn’t. If they expected high pain and got it, they might expect even more pain the next time. But if they expected high pain and didn't get it, nothing changed.

"You would assume that if you expected high pain and got very little you would know better the next time. But interestingly, they failed to learn," said Wager.

Researchers say the study was the first to demonstrate the dynamics of a feedback loop between pain expectations and neural mechanisms that cause pain. Although the test only involved short-term acute pain, researchers say the findings may help explain why chronic pain can linger long after damaged tissues have healed.

"Our results suggest that negative expectations about pain or treatment outcomes may in some situations interfere with optimal recovery, both by enhancing perceived pain and by preventing people from noticing that they are getting better," said Jepma. "Just realizing that things may not be as bad as you think may help you to revise your expectation and, in doing so, alter your experience.”

Gene Therapy Eases Chronic Pain in Dogs

By Lisa Marshall, University of Colorado at Boulder

When Shane the therapy dog was hit by a Jeep, life changed for him and his guardian, Taryn Sargent.

The impact tore through the cartilage of Shane's left shoulder. Arthritis and scar tissue set in. Despite surgery, acupuncture and several medications, he transformed from a vibrant border collie who kept watch over Sargent on long walks to a fragile pet who needed extensive care.

"Sometimes he would just stop walking and I'd have to carry him home," recalls Sargent, who has epilepsy and relies on her walks with Shane to help keep her seizures under control. "It was a struggle to see him in that much pain."

Today, 10-year-old Shane's pain and reliance on medication have been dramatically reduced and he's bounding around like a puppy again, 18 months after receiving a single shot of an experimental gene-therapy invented by CU Boulder neuroscientist Linda Watkins

shane and taryn sargent (casey cass/cu boulder)

shane and taryn sargent (casey cass/cu boulder)

Thus far, the opioid-free, long-lasting immune modulator known as XT-150 has been tested in more than 40 Colorado dogs with impressive results and no adverse effects. With human clinical trials now underway in Australia and California, Watkins is hopeful the treatment could someday play a role in addressing the nation's chronic pain epidemic.

"I'm hoping the impact on pets, their guardians and people with chronic pain could be significant," said Watkins, who has worked more than 30 years to bring her idea to fruition. "It's been a long time coming."

The Role of Glial Cells

Watkins' journey began in the 1980s when, as a new hire in the department of psychology and neuroscience, she began to rock the boat in the field of pain research.

Conventional wisdom held that neurons were the key messengers for pain, so most medications targeted them. But Watkins proposed that then-little-understood cells called "glial cells" might be a culprit in chronic pain. Glial cells are immune cells in the brain and spinal cord that make people ache when they're sick. Most of the time, that function protects us. 

Watkins proposed that in the case of chronic pain, which can sometimes persist long after the initial injury has healed, that ancient survival circuitry somehow gets stuck in overdrive. She was greeted with skepticism.

"The whole field was like 'what on Earth is she talking about?'"

She and her students hunkered down in the lab nonetheless, ultimately discovering that activated glial cells produce specific inflammatory compounds which drive pain. They also learned that, after the initial sickness or injury fades, the cells typically produce a compound called Interleukin 10 (IL-10) to dampen the process they started.

"IL-10 is Mother Nature's anti-inflammatory," she explains. "But in the onslaught of multiple inflammatory compounds in chronic pain, IL-10's dampening cannot keep pace."

Over the years, she and her team experimented with a host of different strategies to boost IL-10. They persisted and, in 2009, Watkins co-founded Xalud Therapeutics. Their flagship technology is an injection, either into the fluid-filled space around the spinal cord or the site of an inflamed joint, that delivers circles of DNA in a sugar/saline solution to cells, instructing them to ramp up IL-10 production.

With financial help from the National Institute of Neurological Disorders and Stroke, the MayDay Fund and CU's Technology Transfer Office – which has provided intellectual property support, assistance with licensing agreements, and help obtaining a $100,000 research grant in 2018 – Watkins is edging closer to bringing her idea to clinical practice.

She has teamed up with veterinary chronic pain specialist Rob Landry, owner of the Colorado Center for Animal Pain Management in Westminster, to launch the IL-10 research study in dogs.

Their results have not been published yet. But thus far, the researchers say, the results look highly promising.

"They're happier, more engaged, more active and they're playing again," said Landry, as he knelt down to scratch Shane's belly after giving him a clean bill of health.

With Shane able to accompany her on her walks again, Sargent has also seen her quality of life improve. Her seizures, which increased in frequency when Shane was injured, have subsided again.

linda watkins with shane (casey cass/cu boulder)

linda watkins with shane (casey cass/cu boulder)

Human Studies Underway

Because the treatment is so localized and prompts the body's own pain-killing response, it lacks the myriad side effects associated with opioids – including constipation and dependency – and it can last for many months after a single injection.

Ultimately, that could make it an attractive option for people with neuropathic pain or arthritis, Watkins says.

This summer, Xalud Therapeutics launched the first human study in Australia, to test the safety, tolerability and efficacy of the compound. Another one-year clinical trial of 32 patients with osteoarthritis of the knee is now underway in Napa, California.

More research is necessary in both pets and people, Watkins stresses. But she's hopeful.

"If all goes well, this could be a game-changer."