Author Archives: PainRelief.com

Study Identifies New Compound That Alleviates Chronic Pain in Preclinical Models

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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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Physical Therapy After Knee Replacement Linked to Less Long Term Opioids for Pain Relief

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PainRelief.com Interview with:
Deepak Kumar, PT, PhD
Assistant Professor, Physical Therapy
Assistant Professor, BU School of Medicine
Director, Movement & Applied Imaging Lab

Dr. Kumar

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

Response: We investigated the association of physical therapy interventions with long-term opioid use in people who undergo total knee replacement surgery.   For people with advanced osteoarthritis, total knee replacement is the only option. The number of total knee replacement surgeries has been increasing and is expected to rise exponentially over the next few years with an aging population and rising rates of obesity. However, up to a third of patients continue to experience knee pain after this surgery. Also, a significant proportion of people become long-term opioid users after total knee replacement. Reliance on opioids may reflect a failure of pain management in these patients. Given that physical therapy interventions are known to be effective at managing pain due to knee osteoarthritis, we wanted to study whether physical therapy before or after surgery may reduce the likelihood of long-term opioid use.

We used real-world data from insurance claims for this study. In our cohort of about 67,000 patients who underwent knee replacement between 2001-2016, we observed that, receiving physical therapy within 90 days before surgery or outpatient physical therapy within 90 days after surgery were both related to lower likelihood of long-term opioid use later. We also observed that initiating outpatient physical therapy within 30 days and 6 or more sessions of physical therapy were associated with reduced likelihood of long-term opioid use compared to later initiation or fewer PT sessions, respectively. However, we did not see an association between type of physical therapy. i.e., active (e.g., exercsise) vs. passive (e.g., TENS) and long-term opioid use.

Importantly, most of our findings were consistent for people who had or had not used opioids previously. We also were able to account of a larger number of potential factors that could confound these associations because of the large sample size. However, there are limitations to our work. Since we only had access to insurance claims data but not to health records, we are unable to make any inferences about association of physical therapy with pain or quality of life, etc.

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UCI Scientists Discover Pathway Blocking Transition from Acute to Chronic Pain

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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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Brainstem’s Role in Placebo and Pain Perception Highlighted

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PainRelief.com Interview with:
Lewis Crawford, B.Sci (Hons), PhD Candidate 
Neural Imaging Laboratory | Faculty of Medicine and Health
University of Sydney 

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

Response: This study was performed as a means to accurately and robustly define the areas of the brainstem responsible for alleviating and enhancing pain via conditioning and expectation alone, that is, the phenomena of placebo analgesia and nocebo hyperalgesia. The reason we were able to do this was by being able to access a 7-tesla ultra-high field MRI, one of only two in Australia, that allowed us to resolve the small nuclei in the brainstem which make up descending analgesic circuitry (they carry signals from your brain to your spinal cord).

We found that a central pathway, comprised of the midbrain Periaqueductal Gray (PAG) and Rostral Ventromedial Medulla (RVM), acted during both phenomena, however in opposite ways. We also identified several other nuclei as playing a role in the modulation of pain which, prior to this study, had not been explored or suggested to play a role in this context. We believe that the brainstem circuitry we defined here enables further research into mechanisms responsible for analgesia and hyperalgesia and will promote further investigation into brainstem function in humans. 

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Astronauts Risk Herniated Discs and Back Pain From Space Flight

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PainRelief.com Interview with:
Dr. Radostin Penchev
Johns Hopkins Medicine

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

Response: Although fewer than 600 people have travelled to space, human space travel is expected to exponentially surge with several companies now offering space excursions as well as with the establishment of the U.S. Space Force in 2019. In parallel with this effort, NASA plans to have a sustained presence on the Moon by 2028.

It turns out that more than 50% of astronauts experience back pain (termed space adaptation back pain) during their mission and are over 4 times more likely to suffer from herniated discs than the normal population. As such, physicians should anticipate a surge in space-related back pathology. More importantly, understanding the cause of back pain in astronauts may also improve the care for other austere environment populations including deep sea divers, fighter pilots and high-altitude explorers.

In this comprehensive review of the literature, we examined the epidemiology, potential causes, and treatments for spinal pain in astronauts.

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Dentists Continue to Prescribe Opioids to Adolescents for Pain Relief

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PainRelief.com Interview with:
Adriane Fugh-Berman MD
Professor, Dept. of Pharmacology and Physiology
Georgetown University Medical Center

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

Response: The first exposure of adolescents and young people to opioids is through dentists, who frequently prescribe opioids after dental procedures. Dentists are the highest prescribers of opioids to patients under 18. We conducted a national survey of dentists and received 269 responses from 30 states and 2 territories.

Four of five dentists knew that  that nonsteroidal anti-inflammatory drug (NSAID)-acetaminophen combinations are equally as effective or more effective than opioids, but 43% still  regularly prescribed opioids. There was more caution about prescribing opioids  to adolescents aged 11 through 18 years, but only half ( 48%) reported they were less likely to prescribe opioids to young adults 19 -25 years (compared to adults over 25). This is concerning  because adolescents and young adults under 25 are more likely to develop opioid use disorder than adults over 25. 

One-half of those who reported prescribing opioids reported prescribing more opioids than needed, which would result in leftover pills. Leftover pills  pose a risk for later misuse. 

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Tramadol Prescriptions for Pain Relief Linked to More Complications than Codeine

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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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Survey of Medical Cannabis Effects on Anxiety and Depression

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PainRelief.com Interview with:
Erin Martin Ph.D. Candidate
Department of Neuroscience
Medical University of South Carolina
Charleston, SC 29425

Erin Martin

PainRelief.com:  What is the background for this study?
Response: Anxiety and depressive disorders are highly prevalent. People with these disorders are increasingly using cannabis products for symptom management, either as an alternative to or in conjunction with traditional antidepressants.

The goal of this study was to examine the effect of medicinal cannabis product use on symptoms of anxiety and depression in a clinical population, and to assess important correlates of anxiety and depression such as chronic pain and quality of life.  

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Study Finds Medical Cannabis Not Likely to Solve Opioid Crisis for Pain Patients

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PainRelief.com Interview with:
Carsten Hjorthøj, senior Researcher
Copenhagen Research Center for Mental Health – CORE, Mental Health Center Copenhagen, Copenhagen University Hospital
University of Copenhagen, Department of Public Health
Section of Epidemiology, Copenhagen, Denmark.

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

Response: Denmark introduced a pilot program of medical cannabis in 2018. Medical cannabis, and cannabis-based medicine, has gained a lot of both attention and controversy as a possible way to treat pain disorders, but the evidence base is still sparse. The Danish nationwide unselected registers allow us to perform a high quality pharmacoepidemiologic study with propensity score matched controls.

The main findings are that medical cannabis and cannabis-based medicine did not reduce the use of opioids in pain patients, and might actually lead to an increase in use of opioids. However, patients with neuropathic pain disorders appeared to reduce their use of gabapentin, their use of overall medication (but not opioids!), and the number of days spent in hospital, compared with controls.

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Back Pain: Advice and Education Provide Small Short-Term Improvements in Pain and Disability

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PainRelief.com Interview with:
Caitlin Jones PhD Candidate
The University of Sydney
Faculty of Medicine and Health, Sydney School of Public Health
Institute for Musculoskeletal Health
Royal Prince Alfred Hospita
Australia

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

Response: Despite advice being recommended internationally as a treatment for spinal pain, the evidence behind that was uncertain and out of date. We didn’t think that the strong and widespread recommendation to provide advice was reflective of the available evidence. There have been multiple, more recent, trials of advice and education with varying results, so it was a good time to collate and summarise these with a systematic review.

Our main findings were that advice and education had a small effect on pain and disability compared to no advice and education, or placebo in the short term. The effects were around 10 points of improvement for pain and 5 points for disability on a 0 to 100-point scale. There was evidence of no effect at all other time points (immediate, intermediate and long term). The specific content of the advice didn’t seem to make much difference.

We compared simple contemporary advice (such as advice to keep active and to avoid bed rest and reassurance about the positive prognosis) to more comprehensive advice, such as ergonomic advice (specific postural and biomechanical information) or pain neuroscience education, and found them all to be about equally effective. Whether the participants’ symptoms were acute or chronic, the intensity of the intervention in terms of time spent with a therapist, how the intervention was delivered and the depth and type of the content didn’t impact outcomes.

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