Adults, especially older adults, may be in pain or depressed but not able to convey details of their symptoms and quality of life to their doctors for various reasons including cognitive impairment. A new study from Regenstrief Institute and Indiana University School of Medicine researchers investigates whether adult patients and their proxies – typically spouses, children or other family caregivers – agree on what they tell physicians about a patient’s symptoms and quality of life, information critical to clinical care.

The researchers found that patients and caregiver proxies agreed on severity of symptoms of pain, depression and anxiety as well as functional status between 50 to 60 percent of the time, with agreement on physical symptoms (pain and functionality) more likely than agreement on psychological symptoms (depression and anxiety).

Proxies tended to overestimate patient impairment at lower levels of symptom severity and underestimate at higher levels. Caregivers who were under a lot of stress were more likely to over-report their patient’s symptoms.

“Unlike blood pressure and blood sugar, symptoms like pain, depression or anxiety can’t be objectively measured,” said Regenstrief Institute and IU School of Medicine faculty member Kurt Kroenke, M.D., who led the study. “Our group is very interested in symptoms – signs you can’t measure with an X-ray or a lab test. The only way to determine severity is with validated scales and if patients can’t report for themselves, then the proxy’s report is an important tool available to the clinician treating the patient.”

Even when a patient is able to self-report, complementary observations from a proxy providing a confirming or disagreeing perspective may inform treatment decisions, according to Dr. Kroenke, a primary care physician.

The study of 576 older adult and proxy participants (188 patient-caregiver pairs as well as 200 patients without identified caregivers) also found that when looking at group averages, patients’ self-reports and caregivers’ reports on patients were in line with each other because over and under reporting averaged out. Dr. Kroenke notes that this confirms the value of using proxy reports in research studies.

Paired patients and their caregivers who were White were 50 percent of study participants. An almost even percentage, 47 percent of the paired patients and 48 percent of their caregivers, respectively, were Black.

“Similar to what occurred during the pandemic, when we used rapid COVID tests rather than the more accurate PCR tests to make decisions about travel or attending events or other issues, because rapid tests were the best we had on hand, when patients can’t complete a symptom scale, proxy reports, while not the best, are the best available and provide valuable information,” said Dr. Kroenke.

The soft flexible device bends and stretches with the body, without the need for bulky, rigid hardware. CREDIT Northwestern University

A Northwestern University-led team of researchers has developed a small, soft, flexible implant that relieves pain on demand and without the use of drugs. The first-of-its-kind device could provide a much-needed alternative to opioids and other highly addictive medications.

The biocompatible, water-soluble device works by softly wrapping around nerves to deliver precise, targeted cooling, which numbs nerves and blocks pain signals to the brain. An external pump enables the user to remotely activate the device and then increase or decrease its intensity. After the device is no longer needed, it naturally absorbs into the body — bypassing the need for surgical extraction.

The researchers believe the device has the potential to be most valuable for patients who undergo routine surgeries or even amputations that commonly require post-operative medications. Surgeons could implant the device during the procedure to help manage the patient’s post-operative pain.

The study will be published in the July 1 issue of the journal Science. The paper describes the device’s design and demonstrates its efficacy in an animal model.

“Although opioids are extremely effective, they also are extremely addictive,” said Northwestern’s John A. Rogers, who led the device’s development. “As engineers, we are motivated by the idea of treating pain without drugs — in ways that can be turned on and off instantly, with user control over the intensity of relief. The technology reported here exploits mechanisms that have some similarities to those that cause your fingers to feel numb when cold. Our implant allows that effect to be produced in a programmable way, directly and locally to targeted nerves, even those deep within surrounding soft tissues.”

A bioelectronics pioneer, Rogers is the Louis Simpson and Kimberly Querrey Professor of Materials Science and Engineering, Biomedical Engineering and Neurological Surgery in the McCormick School of Engineeringand Northwestern University Feinberg School of Medicine. He also is the founding director of the Querrey Simpson Institute for Bioelectronics. Jonathan Reeder, a former Ph.D. candidate in Rogers’ laboratory, is the paper’s first author.

How it works

Although the new device might sound like science fiction, it leverages a simple, common concept that everyone knows: evaporation. Similar to how evaporating sweat cools the body, the device contains a liquid coolant that is induced to evaporate at the specific location of a sensory nerve.

“As you cool down a nerve, the signals that travel through the nerve become slower and slower — eventually stopping completely,” said study coauthor Dr. Matthew MacEwan of Washington University School of Medicine in St. Louis. “We are specifically targeting peripheral nerves, which connect your brain and your spinal cord to the rest of your body. These are the nerves that communicate sensory stimuli, including pain. By delivering a cooling effect to just one or two targeted nerves, we can effectively modulate pain signals in one specific region of the body.”

To induce the cooling effect, the device contains tiny microfluidic channels. One channel contains the liquid coolant (perfluoropentane), which is already clinically approved as an ultrasound contrast agent and for pressurized inhalers. A second channel contains dry nitrogen, an inert gas. When the liquid and gas flow into a shared chamber, a reaction occurs that causes the liquid to promptly evaporate. Simultaneously, a tiny integrated sensor monitors the temperature of the nerve to ensure that it’s not getting too cold, which could cause tissue damage.

“Excessive cooling can damage the nerve and the fragile tissues around it,” Rogers said. “The duration and temperature of the cooling must therefore be controlled precisely. By monitoring the temperature at the nerve, the flow rates can be adjusted automatically to set a point that blocks pain in a reversible, safe manner. On-going work seeks to define the full set of time and temperature thresholds below which the process remains fully reversible.”

Precision power

While other cooling therapies and nerve blockers have been tested experimentally, all have limitations that the new device overcomes. Previously researchers have explored cryotherapies, for example, which are injected with a needle. Instead of targeting specific nerves, these imprecise approaches cool large areas of tissue, potentially leading to unwanted effects such as tissue damage and inflammation.

At its widest point, Northwestern’s tiny device is just 5 millimeters wide. One end is curled into a cuff that softly wraps around a single nerve, bypassing the need for sutures. By precisely targeting only the affected nerve, the device spares surrounding regions from unnecessary cooling, which could lead to side effects.

“You don’t want to inadvertently cool other nerves or the tissues that are unrelated to the nerve transmitting the painful stimuli,” MacEwan said. “We want to block the pain signals, not the nerves that control motor function and enables you to use your hand, for example.”

Previous researchers also have explored nerve blockers that use electrical stimulation to silence painful stimuli. These, too, have limitations.

“You can’t shut down a nerve with electrical stimulation without activating it first,” MacEwan said. “That can cause additional pain or muscle contractions and is not ideal, from a patient’s perspective.”

Disappearing act

This new technology is the third example of bioresorbable electronic devices from the Rogers lab, which introduced the concept of transient electronics in 2012, published in Science. In 2018, Rogers, MacEwan and colleagues demonstrated the world’s first bioresorbable electronic device — a biodegradable implant that speeds nerve regeneration, published in Nature Medicine. Then, in 2021, Rogers and colleagues introduced atransient pacemaker, published in Nature Biotechnology.

All components of the devices are biocompatible and naturally absorb into the body’s biofluids over the course of days or weeks, without needing surgical extraction. The bioresorbable devices are completely harmless — similar to absorbable stitches.

At the thickness of a sheet of paper, the soft, elastic nerve cooling device is ideal for treating highly sensitive nerves.

“If you think about soft tissues, fragile nerves and a body that’s in constant motion, any interfacing device must have the ability to flex, bend, twist and stretch easily and naturally,” Rogers said. “Furthermore, you would like the device to simply disappear after it is no longer needed, to avoid delicate and risky procedures for surgical removal.”

 

“Despite the prevalence and societal costs of pain in the United States, investment in pain medication development is low, due in part to poor understanding of the probability of successful development of such medications,” said the authors of a  study  published Online First in Anesthesiology, the official peer-reviewed journal of the American Society of Anesthesiologists (ASA). “The opioid crisis has highlighted the need for new therapeutics with low abuse potential to treat chronic pain,” they said. “While pharmaceutical companies recognize this need, because of the subjective nature of pain … the conduct of clinical trials for new drug approval is a lengthy and costly proposition.” According to the authors, a better understanding of the probability of the successful development of new pain medications would reduce some of the investment risks.

In the retrospective study, Dermot P. Maher, M.D., M.S., M.H.S., assistant professor, John Hopkins University School of Medicine, Baltimore, and financial engineering colleagues at the MIT School of Management analyzed 469 pain pharmaceutical development programs involving 399 unique active pharmaceutical ingredients between 2000 and 2020. They used publicly available clinical trial metadata from databases provided by Informa Pharma Intelligence to determine the probabilities of success, duration, and survivorship of the pain medication development programs.

The study found that 27.8% of drugs with high abuse potential made it all the way through the development process, compared to only 4.7% of new drugs with low abuse potential. Although the number of drugs with high abuse potential being developed has decreased since the peak of the opioid epidemic in 2010, they are more likely to successfully complete the development process and receive regulatory approval than medications with lower abuse potential. “The higher probability of successful development could represent a more thorough biological understanding of pain signaling pathways targeted by medications with high abuse potential compared to the novel mechanisms offered by alternative medications with lower abuse potential,” they said.

“The opioid crisis was a wake-up call for medicine as a whole,” said Dr. Maher. “On the one hand, we had patients who were simply asking for their pain to be addressed. On the other hand, physicians had very little in their pharmaceutical toolbox that was either remarkably effective, non-addictive or lacked major side effects.”

It’s important to recognize that it is possible to successfully develop pain medications, he noted. “We can increase our understanding of pain mechanisms and target the development of new pain treatments to address this unmet medical need,” said Dr. Maher.

In an accompanying editorial, Michael S. Sinha, M.D., J.D., M.P.H., and Kelly K. Dineen Gillespie, R.N., J.D., Ph.D., echo Dr. Maher’s support for more development of pain medications with better safety profiles. Federally funded research must be conducted to learn more about the biology and mechanisms of pain, they said.

“The National Institutes of Health (NIH) and other research sponsors must allocate funding toward the development of safer analgesics and nonpharmacologic pain management strategies,” they state. “Expanding support for the NIH Helping to End Addiction Long-term (HEAL) Initiative is one way to achieve this goal.”

Changes are also warranted, they assert, “in public and private financing models to encourage and reward interdisciplinary, multimodal, and time-intensive pain treatment programs – programs that are highly effective in enhancing well-being and function but currently scarce in a system that continues to reward fragmented and intervention heavy care. Investment in cross training for providers in pain medicine, substance use disorder treatment, is needed as well as trauma informed care. Innovative, noninvasive biotechnology also holds promise.”

To change the trajectory of pain management research, they conclude, “concerted action by key private and public stakeholders across multimodal treatment domains is the best path forward.”

A newly published study by University of Calgary researchers reveals a potential new way to treat chronic pain using anti-cancer drugs rather than opioid-based pain medication.

By analysing a large number of genes important in the transmission of pain information to the brain, principal investigator Dr. Christophe Altier, PhD, who holds a Canada Research Chair in Inflammatory Pain, and his team have identified the existence of a molecule in the nervous system that enhances sensitivity to pain.

This molecule had previously been thought to play a role in cancer growth but had never been reported in the nervous system. It may now be possible to use already existing anti-cancer drugs to block pain.

“The most exciting part of this discovery is that we don’t need to develop a new drug,” says Dr. Christophe Altier, PhD, associate professor at the Cumming School of Medicine (CSM) and member of the Snyder Institute for Chronic Diseases at the CSM. “We’ve shown that an existing drug, approved in the treatment of cancer, can be repurposed to treat pain.”

In the study on mice, Altier’s team showed drugs commonly used for treating lung cancer and a type of brain cancer could be effective in controlling pain. The researchers specifically tested for pain resulting from nerve injury and inflammation and found the cancer drugs worked very well. The next step is to secure funding for clinical trials to see whether the same positive results will be experienced by people suffering from chronic conditions including abdominal pain and post-surgery pain.

Because the drugs being used already exist and have been proven safe, the timeline for this treatment to become a reality will be shorter than if they had to develop new medications. Altier has already filed a patent application for this novel treatment with study co-author Dr. Gerald Zamponi, PhD, professor at the CSM and member of the Hotchkiss Brain Institute.

The discovery will be welcome news for chronic pain sufferers who in the future might have the option to stop taking potentially addictive opioids that require increases in doses over time to remain effective.

“With these anti-cancer drugs, there is no effect on tolerance,” says Dr. Manon Defaye, PhD, first author on the paper. “We don’t need to increase the dose of the drug to obtain pain relief.”