US Pharm. 2022;47(3):8-12.

Rising Opioid-Overdose Death Rates Among Older Adults

A common stereotype for an “older adult” might include early-bird specials, dentures, and tickets to the matinee show.

A new Northwestern Medicine study that analyzed 20 years of fatal opioid-overdose data in adults aged 55 years and older paints a much different picture. Between 1999 and 2019, opioid-related overdose deaths increased exponentially in U.S. adults aged 55 years and older, from 518 deaths in 1999 to 10,292 deaths in 2019: a 1,886% increase.

“Many of us think drug misuse is a problem of the young. However, older adults are experiencing an explosion in fatal opioid overdoses,” said Maryann Mason, an associate professor of emergency medicine at Northwestern University Feinberg School of Medicine. The findings were published in JAMA Network Open.

In the 20-year span, 79,893 people in the U.S. aged 55 to 80 years died by opioid overdose, with about half being between age 55 and 64 years, Dr. Mason said. The annual overall death rate per 100,000 people aged 55 years and older ranged from a low of 0.9 in 1999 to a high of 10.7 in 2019 and increased annually from 2000 on, the study found.

Lori Post, Buchler Professor of Geriatric Medicine, said ageism is one of the contributing factors for the increase in fatal opioid overdoses among older adults, explaining that doctors often do not screen for drug misuse during appointments with older people because “it doesn’t fit the stereotype of what it means to be old.”

Black men experienced the largest increases in opioid-overdose deaths among older adults since 2013, the study found. By 2019, the opioid-overdose fatality rate among non-Hispanic black or black males aged 55 years and older was 40.03 per 100,000 population—four times greater than the overall opioid fatality rate of others of the same age.

Dr. Mason added that black men are also more likely to have experienced trauma, lack access to health insurance and healthcare, not trust healthcare providers, and be undertreated for pain compared with other subpopulations of older adults.

The study suggested other contributing factors in the exponential increase among older adults. They could include social isolation and depression; exposure to medically prescribed opioids for chronic conditions such as arthritis and cancer, which increase with age; and declining cognitive function that may interfere with taking opioids as prescribed. In addition, the body’s ability to metabolize opioids decreases with age, meaning that people are more vulnerable to overdose.


Promoting Safer Pain Relief With New Compounds

Scientists at Scripps Research in Florida have created a collection of new pain-relieving compounds that, like morphine and other drugs, provide relief via activation of opioid receptors but without inducing many dangerous and unwanted side effects that have driven opioid-related overdose and deaths.

Writing in the journal Proceedings of the National Academy of Sciences, biochemist Laura Bohn, PhD, and colleagues describe a compound called SR-17018, which activates the same pain-relieving receptor as opioid drugs, including morphine, oxycodone, and fentanyl; however, it binds to opioid receptors in a different way from those drugs, leaving the opioid receptor open and available to the body’s own natural pain-relieving substances, apparently augmenting pain relief. In a study by Pantouli et al published in 2021 in Neuropharmacology, the group showed that the compound performed particularly well in mouse studies of chemotherapy-induced neuropathic pain, the scientists write.

In the current report, the authors have made strides in understanding why these drugs seem so different. “We demonstrate that these compounds bind to a different site on the receptor than a typical opioid. Because of that, they seem to leave the receptor on and yet still receptive to endogenous opioids,” says Dr. Bohn, who chairs the Scripps Research Department of Molecular Medicine in Jupiter, Florida. “In neuropathy pain, we show they are far superior to morphine and oxycodone; moreover, SR-17018 does not decrease breathing.”

The authors also described a related compound that, being more potent, induces respiratory suppression but at higher doses than are needed to relieve pain. Importantly for safety, this compound, SR-14968, proved responsive to the overdose-rescue medication naloxone when given at doses high enough to suppress breathing.

Perhaps most importantly for people with severe chronic pain, SR-17018 showed an ability to provide sustained pain relief over time without development of tolerance, the problem of reduced efficacy over time that requires increased dosages, increasing the danger of overdose.

Going forward, the team is continuing to refine and test the compounds so that they could eventually be tested in a clinical setting.

“Severe and chronic pain associated with surgery, nerve damage, and trauma require strong pain relief,” Dr. Bohn says. “Safer solutions are needed. We believe these new compounds are a big step in the right direction.”


New Treatment Reduces Long-Term Pain Following Knee Surgery

With one in five people experiencing ongoing pain long after knee-replacement surgery, new research, led by the University of Bristol and North Bristol NHS Trust in the U.K. and published in The Lancet Rheumatology, has shown a way to help reduce continuing pain that could also save the NHS time and money.

Each year, 100,000 knee-replacement surgeries are carried out in the U.K. Most of these operations take place to treat pain related to osteoarthritis. Unfortunately, every year around 20,000 people who have knee-replacement surgery to relieve their pain find that they have moderate to severe pain 3 months or longer after their operation, which impacts their everyday lives.

The study found the STAR (support and treatment after joint replacement) care pathway reduces pain severity, the amount pain interferes with people’s lives, and is cost effective. The new treatment could potentially save the NHS up to £14 million ($19 million) per year through reduced inpatient admissions.

The study found that patients who received the STAR care pathway had less pain severity and impact on daily life at both 6 and 12 months after treatment (9 and 15 months after surgery); half the number of hospital readmissions; reduced length of hospital stay for any inpatient admissions 3 months after surgery; and less unpaid time off work.

The program looked at how likely patients are to experience ongoing knee pain after their operation and discovered why they avoid seeking help. The research team developed a new treatment—a care pathway—and compared how patients did on the STAR care pathway when compared with a control group who had the usual care.

As part of the STAR care pathway, 3 months after surgery patients attended an hour-long clinic run by specially trained healthcare professionals, and detailed pain questionnaires were filled out and x-rays were taken as well as a blood test for infection. If needed, patients were referred for ongoing treatment. In addition, patients received up to six phone calls over the next 12 months, making sure they had their referral and to check on how they were doing.


Might a Dangerous Microbe Offer a New Way to Suppress Pain?

Anthrax has a scary reputation. Widely known to cause serious lung infections in humans and unsightly, albeit painless, skin lesions in livestock and people, the anthrax bacterium has even been used as a weapon of terror.

Now the findings of a new study suggest that the dreaded microbe also has unexpected beneficial potential—one of its toxins can suppress multiple types of pain in animals.

The research reveals that this specific anthrax toxin works to alter signaling in pain-sensing neurons and, when delivered in a targeted manner into neurons of the central and peripheral nervous system, can offer relief to animals in distress.

The work, led by investigators at Harvard Medical School (HMS) in collaboration with industry scientists and researchers from other institutions, was published in Nature Neuroscience.

Furthermore, the team combined parts of the anthrax toxin with different types of molecular cargo and delivered it into pain-sensing neurons. The technique can be used to design novel precision-targeted pain treatments that act on pain receptors but without the widespread systemic effects of current pain-relief drugs, such as opioids.

“This molecular platform of using a bacterial toxin to deliver substances into neurons and modulate their function represents a new way to target pain-mediating neurons,” said study senior investigator Isaac Chiu, associate professor of immunology in the Blavatnik Institute at HMS.

“There’s still a great clinical need for developing non-opioid pain therapies that are not addictive but that are effective in silencing pain,” said study first author Nicole Yang, HMS research fellow in immunology in the Chiu Laboratory. “Our experiments show that one strategy, at least experimentally, could be to specifically target pain neurons using this bacterial toxin.”

The researchers caution, however, that for now, this approach remains purely experimental and still needs to be tested and further fine-tuned in more animal studies and, eventually, in humans.

For the current study, they started out by trying to determine how pain-sensing neurons may be different from other neurons in the human body. To do so, they first turned to gene-expression data. One of the things that caught their attention: Pain fibers had receptors for anthrax toxins, whereas other types of neurons did not. In other words, the pain fibers were structurally primed to interact with the anthrax bacterium. They wondered why.

The newly published research sheds light on that question while also pointing to novel avenues for drug development beyond the traditional small-molecule therapies that are currently being designed across laboratories.

“Bringing a bacterial therapeutic to treat pain raises the question ‘Can we mine the natural world and the microbial world for analgesics?’” Dr. Chiu said. “Doing so can increase the range and diversity of the types of substances we look to in search for solutions."

Fat Could Inject Relief Into Patients With Plantar Fasciitis Pain

A novel technique that transplants a patient’s own fat into the sole of the foot could offer relief to those suffering from a common and painful condition called plantar fasciitis (PF), according to University of Pittsburgh (Pitt) School of Medicine researchers.

In a pilot study in Plastic and Reconstructive Surgery and led by a wife-and-husband team, the fat-injection procedure improved symptoms of PF in patients, laying the groundwork for a larger clinical trial.

“We developed this procedure to harness the regenerative properties of fat,” said Jeffrey Gusenoff, MD, professor of plastic surgery at Pitt. “In this proof-of-concept study, we showed that fat injections into the foot reduced heel pain, helped patients get back to doing sports and activities, and boosted quality of life.”

“Plantar fasciitis is exceptionally painful,” said Beth Gusenoff, DPM, clinical assistant professor of plastic surgery at Pitt. “When you get up from a sitting position or from sleeping, it’s a sharp, searing pain that some people describe as being like a nail going right through their heel.”

The acute form of PF can be treated with stretching, shoe orthotics, or cortisone injections. But about 10% of patients progress to the chronic form in which the foot’s collagen degenerates and the plantar fascia thickens. For these patients, surgical release of the plantar fascia with a small cut can help, but this surgery comes with risks, according to Dr. Beth Gusenoff.

“Recently, there has been a plea among podiatrists to stop cutting the plantar fascia because some people get a lot of scar tissue, which causes pain,” she explained. “And if too much is cut, the foot can become destabilized, so people end up with almost like a floppy foot.” Inspired by the regenerative properties of fat stem cells, the Gusenoffs developed a technique that uses fat from a patient’s belly or other body area.

To test this method, the team recruited 14 patients with chronic PF and split them into two groups. Group 1 participants received the procedure at the beginning of the study and were followed for 12 months, and their Group 2 counterparts received the procedure after a 6-month observation period and were followed for an additional 6 months.

“We found that Group 1 had improvements in quality of life and sports activity, decreased plantar fascia thickness, and reduced pain levels,” said  Dr. Jeffrey Gusenoff. “And a lot of the measures that were improving 6 months after the procedure got even better by 12 months.”

Pain and Anxiety Affect Breathing on a Cellular Level

Why people’s breathing rate increases dramatically when they are hurting or anxious was not previously understood. Now, a team of Salk Institute scientists has uncovered a neural network in the brain that coordinates breathing rhythm with feelings of pain and fear. Along with contributions to the fields of pain management, psychological theories of anxiety, and philosophical investigations into the nature of pain, these findings could lead to development of an analgesic that would prevent opioid-induced respiratory depression (OIRD), the disrupted breathing that causes overdose deaths.

In the study published in Neuron, the Salk group focused on a group of neurons in the brainstem called the lateral parabrachial nucleus, which is arranged in a core-shell configuration. They found that neurons in the core project to the amygdala, an area of the brain that processes fear and the emotional experience of pain. Neurons in the shell project to the pre–Bötzinger complex, a region that generates breathing rhythm. The core and shell neurons influence each other according to inputs from these areas, making people breathe faster when they experience pain or anxiety.

“We are the first group to demonstrate how the lateral parabrachial nucleus coordinates breathing and pain,” says the paper’s senior author, Sung Han, assistant professor in Salk’s Clayton Foundation Laboratories for Peptide Biology. “By understanding the circuits in this brain region, we may be able to tease apart breathing regulation and pain regulation to develop a medication that inhibits feelings of pain without repressing breathing, like OIRD.”

In OIRD, opioids repress breathing as well as pain; it is the major cause of death from opioids. In previous work, Dr. Han’s laboratory showed that opiates like morphine repress breathing by triggering specific receptors, called mu-opioid receptors (MORs), leading to the inhibition of neurons that express them. It also showed that reactivating the cells that express MORs can reverse OIRD. The current work suggests additional approaches for preventing OIRD, possibly by inhibiting neurons in the region’s core (blunting fear/anxiety) while exciting similar neurons in the shell (supporting breathing).

Dr. Han is eager to see the team’s discovery applied translationally. “The biggest problem these days is that opioids reduce pain but also reduce breathing, so people die,” says Dr. Han, holder of the Pioneer Fund Development Chair. “By understanding those two mechanisms in our research, maybe we can manipulate certain populations of neurons by pharmacological intervention so that we can control pain without changing the breathing.”

Soft Tissue Destruction and Lower Back Pain

Back pain affects many people at some point in their lives, and a common cause is damage to the squishy discs or flexible, rubbery tissues of the spine. However, observing this damage at an early stage is difficult with current imaging methods. Now, researchers reporting in ACS Nano can see microscopic soft tissue destruction in animal spines by targeting denatured collagen with fluorescent molecules.

Any area along the spine, from the neck to tail bone, can become uncomfortable when its soft and protective tissues, including the cartilage and jelly-like intervertebral discs, become damaged and lose their structure. Daily wear and tear, as well as some disorders, such as facet joint osteoarthritis or ankylosing spondylitis, can degrade and unfurl the collagen proteins that give these tissues their bounce and flexibility. Detecting compromised collagen early could help patients get relief before the pain becomes severe, but this is very difficult to do with existing medical technologies, such as x-rays and MRI.

Previously, Yang Li and colleagues developed a collagen hybridizing peptide (CHP) probe that specifically binds unfurled collagen molecules, which happens when they deteriorate and lose their ability to cushion vertebrae. So, Li, Kuibo Zhang, Hong Shan, and colleagues wanted to test if CHP labeled with fluorescent tags could be used as an imaging method to identify collagen destruction in the body.

To make the peptide probe more stable in the body, the researchers modified CHP by substituting a hydroxyl group with fluorine and then attaching a fluorescent dye to it. When healthy mice and rats were injected with the fluorescent dye–labeled CHP and imaged with near-infrared fluorescence, the team confirmed that the fluorescing molecules accumulated on the soft tissues between the vertebrae.

The researchers then removed a portion of the animals’ spines and imaged them with light sheet fluorescence microscopy. This technique produced precise 3D maps, which revealed denatured collagen. Because CHP is known to target damaged collagen, the team says their imaging experiments show that even healthy animals can have a modest degree of deteriorated collagen around load-bearing joints, especially in the lower back.

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