Discovery of Brain Protein Could Lead to New Chronic Pain Treatments

By Pat Anson, PNN Editor

Researchers have identified a protein in the brain that appears to play a prominent role in the maintenance of long-term pain -- a discovery that could lead to new treatments that stop short-term acute pain from progressing to chronic pain.

The protein RGS4 (Regulator of G protein signaling 4) is found in brain circuits that process pathological pain, mood and motivation.

"Our research reveals that RGS4 actions contribute to the transition from acute and sub-acute pain to pathological pain states and to the maintenance of pain," says Venetia Zachariou, PhD, a professor in The Friedman Brain Institute at the Icahn School of Medicine at Mount Sinai in New York City.

"Because chronic pain states affect numerous neurochemical processes and single-target drugs are unlikely to work, it's exciting to have discovered a multifunctional protein that can be targeted to disrupt the maintenance of pain."

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In studies on genetically modified mice, Zachariou and her colleagues found that genetic inactivation of RGS4 did not affect acute pain, but it promoted recovery from nerve injuries, chemotherapy-induced neuropathy and peripheral inflammation. Mice lacking RGS4 developed all the expected symptoms of a nerve injury, but recovered within 3 weeks and returned to physical activity.

The transition from acute to chronic pain is accompanied by numerous adaptations in immune, glial and neuronal cells, many of which are still not well understood. Chronic pain patients experience a number of debilitating symptoms besides pain, such as sensory deficits, depression and loss of motivation

Researchers believe future drugs that target RGS4 could prevent acute pain from transitioning to chronic pain. Currently available medications for chronic pain only treat the symptoms – not the underlying condition – and have major side effects.

Dr. Zachariou's laboratory is conducting further investigation into the actions of RGS4 in the spinal cord and mood-regulating areas of the brain to better understand the mechanism by which the protein affects sensory and pain symptoms.

Their findings are published online in The Journal of Neuroscience.

Study: Prescription Drug Databases Overestimate Opioid Misuse

By Pat Anson, PNN Editor

Prescription drug monitoring has long been seen as the gold standard for tracking the opioid crisis. Patients who fill an opioid prescription for more than three months are considered long-term users with a higher risk of misuse, addiction and overdose. Many pharmacy chains assign a “risk score” to these patients and their doctors could even get a warning letter from the government.

But in a small study of emergency room patients, Canadian researchers found the risk of opioid misuse by long-term users is small and one out of five patients who fill opioid prescriptions don’t even use them. Their findings suggest that prescription databases alone are a poor way to measure opioid misuse.

“The rate of long‐term opioid use reported by filled prescription database studies should not be used as a surrogate for opioid misuse,” said lead author Raoul Daoust, MD, a professor and researcher in the Department of Family Medicine and Emergency Medicine at the University of Montreal.

Daoust and his colleagues surveyed 524 patients who were discharged from a hospital emergency department (ED) with an opioid prescription for acute pain. Instead of just relying on a database to track their prescriptions, the researchers asked the patients about their opioid use.

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Three months after discharge, only 47 patients – about 9 percent – said they were still using opioids. Of those, 72% said they used opioids to treat their initial pain and 19% were using the drugs to treat a new pain condition.

The remaining four patients said they used opioids for another reason, suggesting possible misuse. That’s less than one percent (0.8%) of the original 524 patients.

“Within the limit of our study, our results suggest that the risk of long‐term opioid use for reasons other than pain is low for ED discharged patients with an opioid prescription treating an acute pain condition,” Daoust reported in the journal Academic Emergency Medicine.

Daoust’s findings are controversial because they throw into question the widely accepted theory that all opioid prescribing is risky, whether it’s for chronic or acute pain. The methodology used in his study was questioned by one critic.

"Emergency physicians should not be reassured by the authors' findings. The lack of a denominator, poor response rate (56%), and applied definition of misuse are significant limitations,” said Gail D'Onofrio, MD, a professor of emergency medicine and chair in the department of emergency medicine at Yale University.

D'Onofrio cites a 2017 CDC study, which found that the probability of long-term opioid use increases sharply after the first few days of treatment.

“Transitions from acute to long-term therapy can begin to occur quickly: the chances of chronic use begin to increase after the third day supplied and rise rapidly thereafter,” CDC researchers warned.

But that analysis is based solely on the number of opioid prescriptions – not actual opioid use. And Daoust found that studies like that are a poor way to measure risk.

“These studies used filled prescriptions databases that could overestimate opioid use since not all patients filling an opioid prescription consumed them. As a case in point, in this study, 21% of patients who filled their opioid prescription after the initial ED visit did not consume them,” Daoust reported.

What is the risk of long-term opioid use after an emergency room visit? In a large 2017 study by the Mayo Clinic, only about 1 percent of ER patients given an opioid prescription progressed to long term use – similar to what Daoust found.

"Our paper lays to rest the notion that emergency physicians are handing out opioids like candy," said lead author Molly Moore Jeffery, PhD, scientific director of the Mayo Clinic Division of Emergency Medicine Research. “Most opioid prescriptions written in the emergency department are for shorter duration, written for lower daily doses and less likely to be for long-acting formulations."

A 2018 study also questioned the value of prescription drug monitoring programs (PDMPs) which have long been promoted as critical tools in the fight against opioid abuse. The study found little evidence that PDMPs are reducing overdoses and that they may lead to unintended consequences such as patients turning to street drugs for pain relief.

Pain Clinic Sign ‘Unauthorized and Untrue’

By Pat Anson, PNN Editor

A Florida-based chain of surgery centers and pain clinics says a sign that briefly appeared at one of its clinics implying that the company would no longer prescribe opioid medication is unauthorized and untrue.

The sign appeared in a window at Physician Partners of America’s Jacksonville clinic on May 14.  Someone took a picture of the sign and posted it online, where it was widely shared on Twitter and Facebook among pain patients, advocates and doctors.

“ATTENTION ALL PATIENTS,” the sign said in bold red letters. “Per our chief (medical) officer, Dr. Rivera, we will be starting to focus on interventional medicine only and we will not be managing medication. This will be fully effective within the next 30 days or less.”

For someone taking opioid medication for chronic pain, the threat of being cutoff is very real. The potential number of patients that would be impacted would also be significant. Physician Partners of America (PPOA) treats around 20,000 patients in Florida and Texas.

The problem with the sign is that it isn’t true, according to the company.

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“This sign was brought to our attention through social media. It was in no way authorized or approved by management, and its message is untrue. It resulted from an employee’s misinterpretation of our goal to reduce opioid dependence,” Maria Hickman, PPOA’s social media and content specialist, said in a statement on the company’s website.

“We recognize the opioid crisis backlash. As an organization, we sympathize with the plight of people who rely on, but who do not intentionally abuse, prescription opioid medications to manage their chronic pain. We aim to show them what we consider a better, safer way to reduce or eliminate pain.”

That “safer way” is interventional pain management, a more aggressive form of treatment that includes epidural steroid injections, nerve blocks, “minimally invasive” spinal procedures, Botox injections, spinal cord stimulators and stem cell therapy. Interventional methods are more expensive than pain medication, are not always covered by insurance, and many patients believe they are neither safer or effective.

PPOA said it would continue prescribing opioids to patients when it is appropriate, adding that they would be tapered to lower doses. “Patients are and will continue to be titrated down according to CDC guidelines; however, there is no cut-off date,” Hickman said.

That part of the company’s statement reflects a common misconception about the CDC’s controversial guideline, which is voluntary and does not mandate tapers. The 2016 guideline only recommends tapering “if benefits do not outweigh harms of continued opioid therapy” and explicitly says tapering should be voluntary, with the patient’s consent.

“Clinicians should emphatically review benefits and risks of continued high-dosage opioid therapy and should offer to work with patients to taper opioids to safer dosages. For patients who agree to taper opioids to lower dosages, clinicians should collaborate with the patient on a tapering plan,” the guideline says.

That part of the guideline has been so widely ignored that CDC Director Robert Redfield, MD, released a letter last month warning doctors not to taper patients without their consent.

“The Guideline does not endorse mandated or abrupt dose reduction or discontinuation, as these actions can result in patient harm,” Redfield said. “The Guideline includes recommendations for clinicians to work with patients to taper or reduce dosage only when patient harm outweighs patient benefit of opioid therapy.”

The marketing of Physician Partners of America clearly states a preference for interventional therapy over opioid medication, so patients who go to a PPOA clinic shouldn’t be surprised if tapering or discontinuation is recommended.

“At its foundation, PPOA uses interventional pain management modalities to treat pain at its source instead of masking it with medication,” the company says. “We have championed remedies to the opioid crisis in public forums, in the media, in televised town halls and at medical conventions. PPOA physicians strictly follow the prescribing laws of the states in which they operate.”

A new law recently went into effect in Florida limiting the initial supply of opioids to 3 days, with a 7-day supply allowed if it is medically necessary. However, the law only applies to acute, short-term pain.  Most of PPOA’s patients suffer from chronic back pain and other long-term chronic conditions.

Steep Decline in New Opioid Prescriptions

By Pat Anson, PNN Editor

The number of doctors writing new prescriptions for opioid pain medication has fallen by nearly a third in recent years, according to a large but limited study that documents a dramatic shift in opioid prescribing patterns in the U.S.

Researchers at Harvard Medical School studied health data for over 86 million patients insured by Blue Cross Blue Shield from 2012 to 2017, and found that first-time prescriptions for patients new to opioids – known as “opioid naïve” patients -- declined by 54 percent.

At the start of the study, 1.63% of Blue Cross Blue Shield patients were being treated with new opioid prescriptions. Five years later, only 0.75% were.

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The study also found a shrinking pool of doctors willing to start opioid treatment. The number of doctors who prescribed opioids for opioid naive patients decreased by nearly 30 percent, from 114,043 to 80,462 providers.

The research findings, published in The New England Journal of Medicine, do not provide any context on the patients’ health conditions or the severity of their pain and injuries. As such, it is a data-mining study that provides no real information on the harms or benefits of opioids.

"The challenge we have in front of us is nothing short of intricate: Curbing the opioid epidemic while ensuring that we appropriately treat pain," lead investigator Nicole Maestas, PhD, an associate professor of health care policy at Harvard Medical School, said in a statement. "It's a question of balancing the justified use of potent pain medications against the risk for opioid misuse and abuse."

First-time prescriptions for opioids are usually used to treat short-term acute pain caused by trauma, accidents or surgery. They rarely result in long-term opioid use or addiction, but have become a major target for healthcare policymakers and anti-opioid activists. Several states have adopted regulations that limit the initial supply of opioids to 7 days or less.

While the number of doctors starting opioid therapy has fallen dramatically, Harvard researchers say many are still engaged in “high-risk prescribing” – which they defined as new prescriptions for more than 3 days’ supply or a daily dose that exceeds 50 morphine milligram equivalent (MME).

More than 115,000 of these “high-risk prescriptions” were written monthly for Blue Cross Blue Shield patients. Over 7,700 of the prescriptions exceeded 90 MME per day, a dose that researchers say puts patients at a substantially higher risk of an overdose. The study did not identify whether any of those high-dose patients experienced an overdose.

Opioid prescriptions in the U.S. have fallen sharply since their peak in 2010, but have yet to slow the rising tide of overdoses. Nearly 49,000 Americans died from opioid overdoses in 2017, over half of them due to illicit fentanyl and heroin, not prescription opioids.

Fed Panel Releases Draft Report on Pain Management

By Roger Chriss, PNN Columnist

A federal advisory panel known as the Pain Management Best Practices Inter-Agency Task Force has released a draft report listing its recommendations for improving pain care in the United States. The content is both revealing and promising, because its recognizes the complex nature of chronic pain and the difficulty in treating it effectively.

The task force was formed as a result of the Comprehensive Addiction and Recovery Act (CARA) of 2016. Its mission is to identify gaps and inconsistencies in acute and chronic pain management and to propose possible solutions.

The 29 members who serve on the task force include representatives from the FDA, CDC, VA and Office of National Drug Control Policy; as well as academic and medical experts in pain management, addiction treatment, pharmacy, oncology, psychiatry and interventional medicine.

Interestingly, Harold Tu, MD, the lone dentist on the panel, is the father-in-law of Andrew Kolodny, MD, the founder and Executive Director of Physicians for Responsible Opioid Prescribing (PROP). Only one pain patient and advocate was appointed to the task force, Cindy Steinberg of the U.S. Pain Foundation.

PAIN MANAGEMENT INTER-AGENCY TASK FORCE

PAIN MANAGEMENT INTER-AGENCY TASK FORCE

The key findings of the task force are that pain management should be balanced, individualized, multidisciplinary and multi-modal. Pharmacological pain management requires careful screening and monitoring of patients to minimize risks, while non-pharmacological modalities, in particular physical therapy, also have a significant role to play. The needs of special populations such as children, women, older adults, and military personnel and veterans must also be recognized, according to the draft report.

The task force introduces a new term: “chronic relapsing pain conditions.” These conditions include a lengthy list of degenerative, inflammatory and neurologic conditions, such as multiple sclerosis, cancer, trigeminal neuralgia, lupus, Parkinson’s disease, postherpetic neuralgia, CRPS, porphyria, lupus, lumbar radicular pain, migraines and cluster headaches.

In other words, the draft report recognizes that pain is heterogeneous and the umbrella term of “chronic pain” is problematic. The report notes: “There are multiple potential causes of worsening pain that are often not recognized or considered. Non-tolerance-related factors include iatrogenic (medical related) causes such as surgery, flares of the underlying disease or injury, and increased ergonomic demands or emotional distress.”

The draft report gives considerable attention to the risks associated with high opioid doses and the use of benzodiazepines, but doesn’t entirely dismiss their use:

“Dose-dependent opioid overdose risk among patients increased gradually and did not show evidence of a distinct risk threshold. Much of the risk at higher doses appears to be associated with co-prescribed benzodiazepines.”

“Although the risk of overdose by benzodiazepine co-prescription with opioids is well established, this combination may still have clinical value in patients who have chronic pain and comorbid anxiety, which commonly accompanies pain, and in patients who have chronic pain and spasticity.”

The draft report also warns that medication shortages are worsening the quality of pain care: "Recurrent shortages in opioid and nonopioid medications have created barriers to the proper continuity of treatment in acute and chronic pain patients. This creates the unintended consequence of poor patient care.”

Importantly, the report devotes an entire section to the impact of the 2016 CDC opioid prescribing guideline. While recognizing the “useful general guidance” in it, the report notes that “an unintended consequence of the guideline is the forced tapering or patient abandonment that many patients with chronic pain on stable long-term doses of opioids have experienced."

The report concludes that the “CDC guideline was not intended to be model legislation for state legislators to enact,” but stops short of recommending that the guideline be revised. Instead, the task force recommends “educating stakeholders” about the intent of the guideline and its “core beneficial aspects.”

The depth of analysis in the draft report is clear from the 446 footnoted references, which includes the familiar names of Beth Darnall, PhD, Roger Chou, MD, and Lynn Webster, MD. Pain News Network is even cited as one reference.

The task force held two public hearings in May and September 2018. The task force will be accepting comments on its draft report by mail, email and online. After a 90-day public comment period, the report will be finalized and submitted to Congress.

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Roger Chriss lives with Ehlers Danlos syndrome and is a proud member of the Ehlers-Danlos Society. Roger is a technical consultant in Washington state, where he specializes in mathematics and research.

The information in this column should not be considered as professional medical advice, diagnosis or treatment. It is for informational purposes only and represents the author’s opinions alone. It does not inherently express or reflect the views, opinions and/or positions of Pain News Network.

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.

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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.”

FDA Approves Controversial New Opioid

By Pat Anson, PNN Editor

The U.S. Food and Drug Administration has approved a controversial new opioid drug intended to relieve moderate to severe pain in wounded soldiers and trauma patients. 

Dsuvia is a tablet form of the potent opioid sufentanil. It was developed by AcelRx Pharmaceuticals and the Department of Defense – in part to treat battlefield wounds – but became embroiled in the national hysteria over opioid drugs and addiction.

Dsuvia was developed to fulfill an unmet need in military and civilian hospitals, where patients in acute pain are usually treated with opioids intravenously or with a pill.

Each Dsuvia tablet comes in a single dose plastic applicator. The tablet is taken sublingually under the tongue, where it quickly dissolves and is absorbed into the body.

“There is currently no way available to rapidly treat your pain without sticking you with a needle,” said Dr. Pamela Palmer, an anesthesiologist who co-founded AcelRx and is Chief Medical Officer.

ACELRX image

ACELRX image

“If you broke your femur and are obese or elderly or on a blood thinner, that can be very painful with a lot of bruising. If you take a pill, you have to swallow it with water and wait for it to kick in, which could take up to an hour. Right now, that’s all that’s available. For the first time, we’ve developed a small tablet that goes under the tongue and dissolves in about six minutes.”

“The FDA has made it a high priority to make sure our soldiers have access to treatments that meet the unique needs of the battlefield, including when intravenous administration is not possible for the treatment of acute pain related to battlefield wounds,” said FDA commissioner Scott Gottlieb, MD.

Dsuvia’s efficacy and safety were tested in two placebo-controlled studies with over 200 patients. The company said the drug was well-tolerated and effective across a range of patient ages and body sizes.

But because Dsuvia is so potent – it’s 10 times stronger than fentanyl – it drew the ire of critics who believe diversion is inevitable.

“We know from looking at other potent opioids that have been put on the market in the last four years that once these drugs get past the FDA, there’s very little, if any, control over them, no matter what the sponsor says prior to the time they come on the market,” Raeford Brown, MD, told ABC News.

Brown is chairman of the FDA advisory committee that voted 10-3 to recommend approval of Dsuvia.  Brown was not present for the vote, but called on the FDA to ignore the panel’s recommendation and stop the approval of “this dangerously unnecessary opioid medication."

“It doesn’t seem reasonable to place another potent opioid on the market at this time, especially when we’re currently still writing 200 million prescriptions for opioids a year,” said Brown.

Politicians also weighed in.

“An opioid that is a thousand times more powerful than morphine is a thousand times more likely to be abused and a thousand times more likely to kill,” said Sen. Ed Markey (D) Massachusetts. “It makes no sense to approve an opioid painkiller that has no benefits over similar medications and against the advice of experts.”

The FDA is requiring that Dsuvia not be dispensed for home use, should only be administered by a healthcare provider, and should not be used for more than 72 hours. Palmer says extra precautions would also be taken by distributors, wholesalers and hospitals to prevent theft and diversion.

“I’m not saying that drugs delivered to hospitals never get stolen or abused, but that’s a tiny sliver” of the opioid problem, she said.