PainRelief.com Interview with: Dr Deanne Jenkin PhD UNSW Australia, now Research Fellow at The Daffodil Centre Sydney, Australia
Dr Jenkin
PainRelief.com: What is the background for this study? What are the main findings?
Response: At the time, long-term opioid use for chronic non-cancer pain was increasing and there were signs that their benefit was overestimated whilst the harms were underestimated. Our randomized trial found that after going home from fracture surgery, strong opioids were not better for pain relief compared to a milder, potentially safer opioid alternative.
PainRelief.com Interview with: Amrita Vijay PhD Division of Rheumatology Orthopedics and Dermatology School of Medicine University of Nottingham Nottingham, UK
Dr. Vijay
PainRelief.com: What is the background for this study? What are the main findings?
Response: We carried out this research as we wanted to see if exercise had an effect on the levels of anti-inflammatory substances produced by gut microbes and on endocannabinoids (i.e cannabis-like substances) produced by our bodies.
One of the key findings of the study is that physical exercise increases levels of the body’s own cannabis-type substances and highlights a key link between how substances produced by our gut microbes interact with these cannabis-like substances and reduces inflammation.
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.
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.
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.
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.
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.
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.
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
PainRelief.com Interview with: Ann Z. Bauer ScD Department of Work Environment University of Massachusetts Lowell | UML
PainRelief.com: What is the background for this study? What are the main findings of the underlying studies?
Response: Acetaminophen (paracetamol, brand name Tylenol) is an over-the-counter medication used to relieve pain and reduce fever. It is an active ingredient in over 600 medications and used by more than 50% of pregnant women worldwide and up to 65% of pregnant women in the US.
Current guidance recommends acetaminophen as the pain reliever of choice during pregnancy, as other pain relievers such as ibuprofen and aspirin are contraindicated during pregnancy, particularly after 20 weeks.
In this consensus statement the authors reviewed the research on acetaminophen use during pregnancy from 1995 through 2020 and found a growing body of evidence that suggests prenatal acetaminophen exposure may alter fetal development increasing the risk of neurodevelopmental, reproductive and urogenital disorders. Importantly, this review identifies a convergence of evidence from the trifecta of research areas -human cohort studies, in vitro and animal models. This statement asking for precaution and more research was supported by a total of 91 clinicians and researchers (13 authors and 78 signatories) from around the world.
Research suggests acetaminophen is an endocrine disruptor meaning it interferes with the proper functioning of hormones, specifically it is an anti-androgen that can significantly reduce testosterone production. Acetaminophen exposure during pregnancy has been suggested to increase the risk of male undescended testicles (cryptorchidism) and shorter anogenital distance (ADG) a marker of sub-fertility. Additionally, research suggests increased risk of neurodevelopmental disorders primarily attention deficit hyperactivity disorder (ADHD) and related behavioral abnormalities, but also autism spectrum disorder (ASD), language delays, decreased IQ, and conduct disorders.
Many users do not consider acetaminophen to be a medication with potential side effects. There is high usage, in part, because of a perception that use is of negligible risk. However, because use is so common, if acetaminophen is responsible for even a small increase in individual risk it could contribute substantially to these disorders in the overall population.
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