Study Identifies New Compound That Alleviates Chronic Pain in Preclinical Models

PainRelief.com Interview with:
Rajesh Khanna, PhD
Professor and Vice Chair of Research, Department of Pharmacology,
Associate Director of Research, Comprehensive Pain and Addiction Center
University of Arizona 

Dr. Rajesh Khanna,

Starting January 2022:
Professor, Department of Molecular Pathobiology
Director, NYU Pain Center
College of Dentistry New York University

PainRelief.com:  What is the background for this study? 

Response: Chronic pain conditions cause an immense burden on society due to their astonishingly high prevalence and lack of effective treatments. The National Institutes of Health estimates that nearly 100 million people in the United States suffer from chronic pain. Nearly 20-30% of patients prescribed opioids for chronic pain misuse them, according to the National Institute on Drug Abuse.  In 2019, nearly 50,000 people in the U.S. died from opioid-involved overdoses and that number increased to nearly 70,000 in 2020. There is clearly an urgent need for non-addictive treatments for chronic pain.

The voltage-gated sodium channel NaV1.7 is preferentially expressed in the peripheral nervous system within ganglia associated with nociceptive pain. This channel modulates the threshold required to fire action potentials in response to stimuli and has been established as a key contributor to chronic pain. Chronic pain states can result from upregulated NaV1.7 expression which has been shown to occur in association with diabetic neuropathy, inflammation, sciatic nerve compression, lumbar disc herniation, and after spared nerve injury. The exact pathways leading to the dysregulation of NaV1.7 are poorly understood, but likely involve mechanisms related to its surface trafficking and regulation via protein-protein interactions.

Our previous work identified the collapsin response mediator protein 2 (CRMP2) as a novel regulator of NaV1.7 function and uncovered the logical coding of CRMP2’s regulatory functions. We found that if CRMP2 is phosphorylated by cyclin dependent kinase 5 at serine 522 and also modified by SUMOylation at lysine 374 by the SUMO conjugating enzyme Ubc9, then NaV1.7 is functional. When not SUMOylated, CRMP2 recruits the endocytic proteins Numb, Nedd4-2, and Eps15, triggering clathrin mediated endocytosis and internalization of NaV1.7. When not at the cell-surface, sodium currents are reduced, alleviating NaV1.7-associated chronic pain. This action of CRMP2 is highly selective for NaV1.7, as no effects on other voltage-gated sodium channel subtypes are observed.

Previous efforts to target NaV1.7 for pain relief have focused on development of direct channel blockers, but this approach has been unsuccessful. Disclosed reasons for failure of these NaV1.7-targeting drugs include issues with:
(a) central nervous system penetration,
(b) lack of selectivity (e.g., of Biogen’s Vixotrigine),
(c) inadequacy of pain models, and
(d) insufficient channel blockade.

These factors culminate in continued action potential firing and failure to relieve pain, which has led to skepticism regarding targeting of NaV1.7.

We hypothesized that targeting CRMP2 with a small molecule to prevent it’s SUMOylation would be a novel and effective approach to indirectly regulating NaV1.7 for the treatment of chronic neuropathic pain.

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Tramadol Prescriptions for Pain Relief Linked to More Complications than Codeine

PainRelief.com Interview with:
Carlen Reyes PhD
Médico de familia
Gestora de proyectos de investigación IDIAP Jordi Gol

PainRelief.com: What is the background for this study? What are the main findings?

Response: Tramadol and codeine are two “weak” opioids frequently prescribed for different non-cancer pain indications, however, few are the studies that compare the adverse outcomes between them using large routinely collected primary care data. We aimed to fulfil this gap by analysing the risk of adverse events with the tramadol and codeine dispensations in a large primary care health care data (SIDIAP database) from Spain. 

We found that the dispensations of tramadol were associated with a greater risk of cardiovascular events, mortality and fractures compared to the dispensations of codeine. 

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Migraine Pain Linked to Stress Varies by Individual

PainRelief.com Interview with:

Serena L. Orr, MD, MSc, FRCPC, FAHS
Assistant Professor
Depts of Pediatrics, Clinical Neurosciences and Community Health Sciences 
Cumming School of Medicine, University of Calgary
Director, Pediatric Headache Program
Alberta Children’s Hospital

Dr. Orr

PainRelief.com:  What is the background for this study?

Response: Stress has long been felt to be one of the most common trigger factors for migraine. However, there is very little data on the relationship between stress and pain severity in individuals with migraine on a day-to-day basis, and this relationship is even more poorly understood among individuals with more frequent attacks, such as those with chronic migraine (who have at least 15 days/month of headache, 8 or more of which meet criteria for migraine attacks).

This was a study that looked at daily electronic headache diary data for 136 adults with chronic migraine, using data from the N1-Headache application. In this study, we aimed to understand the relationship between perceived stress and pain severity in individuals with chronic migraine. Individuals completed 90 days of daily diary entries where they reported on their headache characteristics, and their perceived stress levels, measured on a scale of 0-10.

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Caution Should Be Taken with Hip Steroid Injections For Arthritis Pain Relief

PainRelief.com Interview with:
Kanu M. Okike, MD
Orthopedic Surgeon
The Hawaii Permanente Medical Group

PainRelief.com:  What is the background for this study?  What are the main findings?

Response: Hip corticosteroid injections are a common treatment for osteoarthritis and other hip conditions.  Recently, isolated case reports have raised the question of whether hip corticosteroid injections could be associated with rapid progression of the arthritis process – a condition known as rapidly destructive hip disease (RDHD).

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Knee Arthritis: Racial Differences in Treatment Patterns and Health Care Expenditures

PainRelief.com Interview with:
Stuart L. Silverman MD FACP FACR
Clinical Professor of Medicine, Cedars-Sinai Medical Center and UCLA School of Medicine
Medical Director, OMC Clinical Research Center
Beverly Hills, CA 90211

Dr. Silverman

PainRelief.com:  What is the background for this study?

Response: As a practicing rheumatologist, I am aware that prior studies have shown variation in medical care, pain management and treatment with opioids by race and social economic status.  Suboptimal treatment of pain in patients with osteoarthritis (OA) may also disproportionately burden racial minorities and Medicaid recipients. 

Studies have shown that African Americans are nearly 1.5 times as likely to have symptomatic knee OA than White patients even when adjusting for other factors.  Similarly, they also have a higher prevalence of symptomatic and radiographic hip OA.  Analyses of Medicare data has shown evidence of persistent racial disparities for joint arthroplasty usage and surgical outcomes.

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Physicians Differently Prescribe Pain Relief Medications to White and Minority Patients

PainRelief.com Interview with:
Dan P. Ly M.D., M.P.P., Ph.D.
Division of General Internal Medicine and Health Services Research
David Geffen School of Medicine
University of California, Los Angeles

PainRelief.com:  What is the background for this study?  What are the main findings?

Response: We know that minority patients were less likely to receive opioids than white patients, but this could have been due to minority patients seeing lower opioid-prescribing physicians. As far as I could tell, nobody had been able to examine whether the same physician prescribed opioids differently to their minority patients.

I find that this is the case: the same physician was less likely to prescribe opioids to their minority patients with new low back pain, and instead was more likely to prescribe NSAIDs to their minority patients. And unfortunately, this differential prescribing may have had the consequence of leading to more chronic opioid use in white patients.  

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Back Pain: SelfBACK app To Help Patients Find Pain Relief From Self-Managed Program

PainRelief.com Interview with:
Louise Fleng Sandal PhD
Adjunkt, Institut for Idræt og Biomekanik
SDU University of Southern Denmark

Dr. Sandal

PainRelief.com:  What is the background for this study?

Response: Low back pain is a globally prevalent condition with a high economic cost. Many people seek help with primary care from their general practitioner, physiotherapist or chiropractor. Evidence-based guidelines on first line treatment include learning to self-manage, staying active, exercising and learning about the condition. However, many find this difficult without advice and support, but primary care physicians often lack the time and resources to support self-management.

Digital solutions, such as smartphone technology, utilizing artificial intelligence can be used to tailor self-management support to the individual and be available at the individuals convenience.

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Chronic Pain Sufferers Face Different Pain Triggers During Pandemic

MedicalResearch.com Interview with:
Rubén Nieto
eHealth Lab Research Group,
Faculty of Health Sciences
Universitat Oberta de Catalunya
Barcelona, Spain

MedicalResearch.com:  What is the background for this study?

Response: The COVID-19 pandemic is one of the most serious global challenges to have faced healthcare and society in the last century, taking a drastic toll on the world’s population. It has caused deaths, worsened people’s quality of life and upended the economy, among other consequences. Despite this, there is little research on how people are coping with the pandemic. In our opinion, it is of particular interest to study people with chronic pain, since COVID-19 and the circumstances surrounding it can have a greater impact on them.

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Pain Suppresses the Activity Of the Brain Reward System

Stéphane Potvin, PhD
Centre de recherche
Institut Universitaire en Santé Mentale de Montréal
Full professor; Department of psychiatry and addiction
University of Montreal

PainRelief.com: What is the background for this study? What are the main findings?

Dr. Potvin: Let’s begin by using a concrete example. First, imagine that you are taking a walk and it is really cold outside; so cold, in fact, that you can no longer enjoy the experience. Upon returning home, you realize that you no longer feel the pain, and you now have a smile on your face. During this sequence of events, what happened in your brain? To figure it out, we performed a functional neuroimaging study during which a painful cold gel was applied on the right foot of a group of healthy volunteers. What we discovered is that during pain stimulation, there was a clear de-activation of the medial orbito-frontal cortex, which is one of the main “pleasure” centers in the brain. Intriguingly, we observed that after the cold pain stimulation was discontinued, participants experienced significant levels of pleasant emotions that lasted for approximately 4 minutes.

Opioid Analgesic Use For Pain Relief in Chronic Noncancer Pain

PainRelief.com Interview with:
Dr Stephanie Mathieson
NHMRC Health Professional Research Early Career Fellow
The University of Sydney
Faculty of Medicine and Health, Sydney School of Public Health
Institute for Musculoskeletal Health
Royal Prince Alfred Hospital Australia

PainRelief.com:  What is the background for this study?

Response: Chronic non-cancer pain, such as chronic non-specific low back pain has a substantial impact on society by costing billions of dollars each year in health care costs and lost productivity.

Current clinical practice guidelines for the management of chronic non-cancer pain, such as those from the Centers for Disease Control and Prevention, now recommend avoiding the initial use of opioid analgesics, as the risk of harms, such as overdose and death.

We wanted to establish the extent to which opioid analgesics are used by people with chronic noncancer pain. This is important, as many studies report how many opioids are prescribed, but this may not represent the actual use of opioid analgesics.

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