Chronic Pain: Sex Differences in Pain Relief from High vs Low Spinal Cord Stimulation

PainRelief.com Interview with:
Imanuel Lerman MD MSc
Associate Professor 
Affiliate Electrical and Computer Engineering 
VA San Diego Healthcare System
Center for Stress and Mental Health
Center for Pain Medicine 
UC San Diego Health 
Qualcomm Institute 
California Institute for Telecommunications and Information Technology (Calit2)

Dr. Lerman

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

Response: Spinal Cord Stimulation (SCS) offers an implantable, non-pharmacologic treatment for patients with intractable chronic pain conditions.  There is extensive clinical literature that offers support for efficacy in chronic pain treatment for both Low frequency and High frequency based  spinal cord stimulation. While Low Frequency SCS has been heavily examined since its inception, High Frequency SCS paradigms have recently been clinically approved.

Emerging preclinical work also show sex may alter certain immunological pathways that contribute to chronic pain.  But to date few report have identified interactions between sex and SCS.  Therefore, we aimed to fill this knowledge gap through a single site (University of California San Diego), large (n=237) retrospective (2004–2020) analyses that compared SCS paradigm Low vs High Frequency SCS, efficacy (pain relief and opiate sparing effects) across sex.

Psychological Interventions For Non-Specific Chronic Low Back Pain

PainRelief.com Interview with:

Ms Emma Ho | BAppSc(Phty)(Hons), PhD Candidate
The University of Sydney                                          
Faculty of Medicine and Health | Charles Perkins Centre Musculoskeletal Research Hub | Sydney NeuroMusculoskeletal Research Collaborative
Faculty of Medicine and Health, The Back Pain Research Team, Sydney Musculoskeletal Health, The Kolling Institute, School of Health Sciences

Emma Ho

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

Response: Adults with chronic low back pain (lasting for more than 12 weeks) not only experience physical disability but can also suffer psychological distress in the form of anxiety, depression, and fear avoidance (avoiding movement for fear of pain).

Clinical guidelines therefore consistently recommend a combination of exercise and psychosocial therapies for managing chronic low back pain. However, not much is known about the different types of psychological therapies available as well as their comparative effectiveness and safety, leaving doctors and patients often unclear about the best choice of treatment. Accordingly, the aim of our systematic review with network meta-analysis was to determine the comparative effectiveness and safety of psychological interventions for chronic non-specific low back pain.

Study Identify Mechanism That Converts Normal to Chronic Pain

PainRelief.com Interview with:
Dr. Daniela Mauceri PH.D.
Neurobiology
Heidelberg University
Heidelberg Germany

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

Response: Physiological, normal, pain prevents damage to the tissues and, in case of injury, resolves with healing. Pathological, chronic pain however, will persist after injury is mended and can manifest even in absence of causes. The transition from physiological to chronic pain is sustained by alterations of gene expression in the cell belonging to the pain circuitry such as neurons of the dorsal horn spinal cord. Epigenetic changes are important mechanisms regulating gene transcription in mammalian cells and had been previously implicated in pain chronification. A detailed understanding of which epigenetic mechanism would be critical in the establishment of chronic pain was still missing and the identity of the regulated genes still elusive.


PainRelief.com:  What are the main findings?

Response: In our study we described how one particular epigenetic molecule named Histone Deacetylase 4 (HDAC4) is inactivated in the neurons of the dorsal horn spinal cord in persistent inflammatory pain. We also showed that inactivation of HDAC4 leads to increased expression of Organic Anion Transporter 1 (OAT1) and found that OAT1 is responsible for the mechanical hypersensitivity typical of chronic pain. 

PainRelief.com: What should readers take away from your report?

Response: Our study suggests that finding ways to maintain HDAC4 in an active state might prevent pain chronification by blunting the upregulation of OAT1. Alternatively, blocking OAT1 activity with a pharmacological approach might also be beneficial.

PainRelief.com: What recommendations do you have for future research as a result of this work?

Response: Chronic pain is a severe pathological condition affecting a considerable part of the worldwide population. Treatments are still unsatisfactory. Our study, although performed using a mouse model of chronic inflammatory pain puts forward two potential new candidates (HDAC4, OAT1) for not only future investigations but also, importantly, for the development of future therapeutic approaches.

The research work was funded by the CRC1158 on Chronic Pain by the German Research Foundation.

Citation:

Litke, C., Hagenston, A.M., Kenkel, AK. et al. Organic anion transporter 1 is an HDAC4-regulated mediator of nociceptive hypersensitivity in mice. Nat Commun 13875 (2022). https://doi.org/10.1038/s41467-022-28357-x

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Study Evaluates Complex Relationship Between Eating and Chronic Pain

PainRelief.com Interview with:
Paul Geha, M.D
Assistant Professor of Psychiatry
University of Rochester Medical Center
Rochester, NY 14620

Dr. Geha

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

Response: Chronic pain and obesity are interrelated; chronic pain is more common in obese individuals and obese individuals have a higher occurrence of chronic pain conditions such as low-back pain.  The mechanisms behind this association are poorly understood.  In this line of work we are trying to offer an explanation for how chronic pain could lead to obesity. 

We build on two previous facts established in the literature to come up with a new theory. 

First, it is well known that the current obesity epidemic is due to overeating in an environment where highly caloric food is cheap and readily available (e.g., fast food).

Second, our brain imaging research on chronic pain patients established that chronic pain affects the brain motivational pathways (or emotional brain) which are directly involved in feeding decisions, especially the ones that come after satiety.  As such, the emotional brain has been implicated in the decision to overeat on top of satiety. We therefore hypothesized that chronic pain would be associated with disrupted eating behavior that could lead to overeating because of changes in the emotional brain of patients. This is a new approach because the prior thinking posited that obesity and chronic pain are interrelated either because of increased inflammation originating from the increased fat mass or from the fear of movement that patients may have leading to a more sedentary lifestyle. While both theories may be correct, they have never been confirmed.

The current paper builds on a finding we published in PAIN 2014 where we established disrupted eating behavior in patients with chronic low-back pain affecting mainly high-fat foods but not sugary drinks.  In that work we asked patients with long-standing history of chronic low-back pain to sample without consumption pudding with increasing concentration of fat and a sugary drink with increasing concentration of sucrose.  While the sensory experience of the food items was normal in the patients, they reported less pleasure (“liking”) from tasting the fatty pudding but not the sugary drink. On a different session, we brought back the patients and offered them to consume as much as they wanted the pudding that they liked the most during the first testing session. Participants were asked to come hungry.   Chronic back-pain patients showed that their liking and hunger ratings did not predict how much they ate.  Healthy controls showed a linear relationship between liking and hunger ratings and how much they ate. 

In the manuscript we just published in PLOS One we continued this line of work to understand how this disrupted eating behavior sets in as low-back pain develops or subsides.  We wanted to know whether disrupted eating behavior develops in conjunction with chronic pain or because of it.  Hence, we recruited patients with new onset low-back pain (6-12 weeks duration) and tested them in the same way described in our PAIN 2014 paper at baseline and then again at one year as some of them recovered from pain while others became chronic low-back pain because pain persisted at one year follow-up.  In this manuscript we also collected brain images that would allow-us to measure volumes of a key structure in the emotional brain, the nucleus accumbens.  The function of the latter structure is to translate our motivation (e.g., wanting to eat) to actions (e.g. the motor response needed to reach for the food). We wanted to know whether we can link the disrupted eating behavior to measures in the emotional brain. This question was based on our previous finding where we observed that patients at risk of becoming chronic pain or patients already in the chronic phase have a compromised accumbens (i.e. smaller than normal).

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As Opioid Prescriptions Fall, Alternate Prescriptions for Pain Relief Increase

PainRelief.com Interview with:
Lauren R. Gorfinkel MPH
New York State Psychiatric Institute
New York, NY
Department of Medicine, University of British Columbia
Vancouver, Canada

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

Response: The opioid crisis has led to clear declines in opioid prescribing across North America, however, chronic pain remains an extremely common health problem with limited treatment options. This study was therefore interested in using nationally-representative data to find out whether alternative pain medications are growing more popular as opioid prescriptions decline.

Cooled Radiofrequency Ablation for Pain Relief After Total Knee Replacement

PainRelief.com Interview with:

Felix Gonzalez, M.D.
Assistant professor, Division of Musculoskeletal Imaging
Department of Radiology and Imaging Scienc
Emory University School of Medicine
Atlanta, Georgia

Dr. Gonzalez

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

Response: Total knee arthroplasty is a common procedure performed worldwide for the treatment of symptomatic knee arthritis. Unfortunately, approximately 20% of those patients develop chronic pain after the surgical intervention in the setting of no complications such as infection or hardware loosening. The reason for this is not known at this point although theories exist.

The new study focused on 21 patients who were experiencing persistent chronic pain after total knee replacement, without underlying hardware complications. The patients had all failed conservative care. They filled out clinically validated questionnaires to assess pain severity, stiffness, functional activities of daily living and use of pain medication before and after the procedure. Follow-up outcome scores were collected up to one year after the C-RFA procedure.

In the end, the study found, patients with knee arthritis reported an 70% drop in their pain ratings approximately, on average.

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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UCI Scientists Discover Pathway Blocking Transition from Acute to Chronic Pain

PainRelief.com Interview with:

Daniele Piomelli PhD Distinguished Professor, Anatomy & Neurobiology Louise Turner Arnold Chair in Neurosciences Joint Appointment, Biological Chemistry and Pharmacology School of Medicine Director, Center for the Study of Cannabis University of California, Irvine
Dr. Piomelli

Daniele Piomelli PhD
Distinguished Professor, Anatomy & Neurobiology
Louise Turner Arnold Chair in Neurosciences
Joint Appointment, Biological Chemistry and Pharmacology
School of Medicine
Director, Center for the Study of Cannabis
University of California, Irvine

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

Response: The pain caused by physical trauma or by surgery can disappear in a relatively short time — or linger for months or even years. In some cases, for example after open heart surgery, the percent of people who develop persistent pain can be as high as 40%. Breast and knee surgery, among others, have similar outcomes. We still don’t understand how acute pain after an injury becomes chronic.  

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Study Addresses How Weather Affects Pain Tolerance

PainRelief.com Interview with:
Erlend Hoftun Farbu, PhD student
Department of Community Medicine
The Arctic University of Norway
Tromsø, Norway

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

Response: Many report that weather affect their pain condition. Some studies confirm this, others do no. However, these studies have asked “How much pain do you have today?”

We used two tests to assess how much pain a person can tolerate. We then looked at how pain tolerance vary over time and if they are associated with weather.

The results show quite clearly that people can tolerate more pain caused by intense cold temperature in the colder months of the year. There was no such seasonal variation in pain caused by pressure to the leg. On the other hand, we found that both pressure pain tolerance and weather at one day was associated with the next days, but not the next month. When we further linked the weather and pain tolerance, we found that, for example, in some periods a rise in temperature happened at the same time as a rise in pain tolerance. While in other periods, there were no such association. We mean that this is because we adapt to the weather. For example, how we experience 5 °C (41°F) is different in autumn and spring..

Finally, temperature and barometric pressure could predict future values of pressure pain tolerance

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Switching to Buprenorphine Might Provide Pain Relief for Poorly Controlled Pain

PainRelief.com Interview with:
Victoria D. Powell, MD, FACP
Clinical Lecturer – Geriatric and Palliative Medicine
University of Michigan
Staff Physician, Palliative Care
LTC Charles S. Kettles VA Medical Center
Ann Arbor, MI

Dr. Powell

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

Response: People with chronic pain who use long-term opioids face a number of health risks, and often do not have optimally controlled pain.

Buprenorphine acts on the opioid receptor with a different effect than drugs like morphine or oxycodone, and as a result is less associated with the risks of long-term opioid use, such as accidental overdose. While buprenorphine has been successfully used in patients with opioid use disorder for several years, certain experts have proposed using buprenorphine for pain management in people with chronic pain. We found low quality evidence supporting pain control that may be superior to traditional opioids, but much more research is needed to confirm.

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