Repurposing Old Drugs May Lead to Chronic Pain Relief Medications

PainRelief.com Interview with:
Shane Cronin PhD
Staff scientist in the Penninger lab at IMBA
Former postdoc in the Woolf lab at Harvard Medical School and
F.M. Kirby Neurobiology Center, Boston Children’s Hospital

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

Response: We and others have shown that the BH4 (tetrahydrobiopterin) metabolic pathway is upregulated in injured nerves and contributes to pain hypersensitivity in various rodent models of chronic pain. BH4 is a metabolite and an important cofactor for the aromatic amino acid hydroxylases for the production of dopamine and serotonin for example. it has also been previously shown to exert cofactor independent roles such as ROS scavenging and Fe3+ reduction in maintaining mitochondrial health.

Moreover, gene association studies in humans have also demonstrated a correlation between low levels of the bottleneck enzyme for BH4 biosynthesis, GCH1, and reduced severity of chronic pain (nicely reviewed here: PMID: 28667479). We believe that targeting this increase of BH4 after nerve injury is a viable strategy to reduce the ensuing pain. So, we set up a screening platform using transgenic mouse DRG neurons in which GFP is controlled by the Gch1 promoter – when Gch1 is turned on (as is in the case of nerve injury), GFP gets turned on as a proxy for BH4 activation and ‘in vitro cellular pain’. 

Use of Nitrous Oxide for Pain Relief During Labor and Delivery Reevaluated in Light of Greenhouse Gas Emissions Concerns

PainRelief.com Interview with:
Prof. Bernd Froessler MD, PhD, FANZCA
Department of Anaesthesia
Lyell McEwin Hospital
Clinical Professor
Discipline of Acute Care Medicine
University of Adelaide

Prof. Bernd Froessler

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

Response: Nitrous oxide (N2O) is commonly used in Australia for labour analgesia. Its use in labour is potentially associated with aerosol generation. During the first wave of the COVID-19 pandemic of 2020, nitrous oxide was suspended on many birthing units to reduce the risk of transmission. This 19-day sudden disruption period at our hospital provided a ‘natural experiment’ and opportunity to re-evaluate the role and need for N2O, with the aim to determine the impact of withdrawing N2O on labour analgesia use and maternal and neonatal outcomes.

Posture and Pill Shape Affect How Quickly Pain Relief Medications Dissolve and Work

PainRelief.com Interview with:
Rajat Mittal Ph.D.
Professor of Mechanical Engineering 
Professor of Medicine (Secondary Appt.)
Johns Hopkins University

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

Response: I have worked on the biomechanics and fluid dynamics associated with many different organ systems in the past including the cardiovascular system, the larynx and cerebral hemodynamics, and there is very extensive research being done on these organ systems by research groups all over the world. However, as I was looking to initiate research in some new directions, the implications of stomach biomechanics on important conditions such as diabetes, obesity, gastroparesis, malnutrition and GI infections etc. became apparent to me.

Furthermore, it was clear that bioengineering research in this arena lags other more established areas such as cardiovascular flows by at least 25 years and there seemed to be great opportunity to do impactful work. We focused on drug dissolution for our first project because it offered  “low-hanging fruit” in terms of new and impactful insights.

Long Covid Symptoms Common, Especially Taste and Smell Issues

PainRelief.com Interview with:
Elizabeth K. Rutkowski, MD MS
Associate Professor of Neurology
Director, Neurology Clerkship
Assistant Director, Adult Neurology Residency Program
Medical College of Georgia
Augusta University Medical Center

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

Response We are looking at the long-term neurological effects of COVID-19. 80% of our subjects reported neurological symptoms with the most commonly reported symptoms being fatigue and headache.

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Headache: Clinical Trial Finds Oral Atogepant Reduced Monthly Migraine Days

Dr. Trugman

PainRelief.com Interview with:

Joel M. Trugman, MD
Associate Vice President
Neuroscience Development
AbbVie

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

Response: Migraine is a disabling chronic disease characterized by recurrent headache attacks and associated symptoms, including nausea, phonophobia, or sensitivity to sound, and photophobia, or sensitivity to light.

The ADVANCE clinical trial is a phase 3, randomized, double-blind, placebo-controlled trial and examined the safety and efficacy of atogepant, an oral, small-molecule calcitonin gene-related peptide receptor antagonist in patients with episodic migraine. The primary efficacy endpoint was the change from baseline in mean monthly migraine days (MMD) across the 12-week treatment period. This analysis that was recently published examined the efficacy of atogepant using 4 levels of mean monthly migraine day (MMD) responder rates. 

This analysis found that all doses of atogepant significantly increased the proportion of participants who achieved a ≥25%, ≥50%, ≥75% and 100% reduction in mean monthly migraine days over 12 weeks of treatment.

More Nonopioid Medications Prescribed for Pain Relief since CDC Released Chronic Pain Guidelines

PainRelief.com Interview with:

JASON GOLDSTICK
Dr. Goldstick

Jason E. Goldstick, PhD
Injury Prevention Center
Department of Emergency Medicine
University of Michigan, Ann Arbor

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

Response: In 2016, the CDC released the Guideline for Prescribing Opioids for Chronic Pain. A primary goal of this voluntary guideline is that individuals should receive pain management care that provides the greatest overall benefit. Among other things, this may entail beginning opioid treatment only when the clinician determines that the expected benefits outweigh the risks.

Other research has shown reductions in opioid prescribing as reduced since the guideline release; this report examines whether there were changes in nonopioid pain medication prescribing.

Our overall findings were that nonopioid prescribing increased nationally following the guideline release, above and beyond what would’ve been predicted based on the pre-guideline trends, and this finding was generally consistent across patient subpopulations (e.g., those with vs. without prior opioid exposure).

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PTSD: Cognitive Behavioral Therapy for Pain Relief from PostTraumatic Headache

PainRelief.com Interview with:
Don McGeary, PhD, ABPP
Vice Chair for Research, Rehab Medicine
Associate Professor, Rehab and Psychiatry
UT Health San Antonio

Don McGeary
Dr. McGeary

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

Response: This was a randomized clinical trial funded as part of the Consortium to Alleviate PTSD.  The primary aim of the study was to test the efficacy of a novel non-pharmacological intervention (called CBT for headache; CBTH) for posttraumatic headache (PTH) attributable to mild traumatic brain injury (mTBI). 

PTH is the most common and disabling consequence of mild traumatic brain injury and is a large concern for military service members and veterans in the post-9/11 deployment era because of the significant increase in head injury in this population over the last 20 years.  Posttraumatic headache has been recognized under various labels (including “shell shock” and “hero’s headache”) for over a century, but there are no proven, frontline treatments for PTH. PTH is unique among headache diagnoses because it is classified as a secondary headache (i.e., develops as a consequence of another medical phenomenon, mTBI) and because it is diagnosed based on the injury that led to the headache with no criteria for specific clinical characteristics.  Thus, the “phenotype” of posttraumatic headache is variable with the most frequent reports describing symptoms consistent with migraine AND tension type headaches. 

Unfortunately, because the underlying mechanisms of PTH differ from the primary headaches they resemble, frontline medications (abortive and prophylactic) may not have the same efficacy for PTH as they do for the primary headaches for which they are usually prescribed.  To complicate things further, PTH is often acquired in the context of a traumatic experience (blast, firearms overpressure, motor vehicle accident, other traumatic injury), so PTSD is highly comorbid with these headaches and there is an evolving body of research showing that PTSD can complicate, maintain and worsen pain.

Thus, our study sought to
(1) Test a novel non-pharmacological intervention tailored to PTH rehabilitation and
(2) Assess the relationship between PTSD and PTH to determine if preferred treatment pathways should include PTSD treatment as well. 

This resulted in a three-arm trial comparing CBTH to a gold-standard non-pharmacological treatment for PTSD and usual care in a large VA polytrauma center.

Relivion Stimulator of Both Occipital and Trigeminal Nerves for Migraine Pain Relief

PainRelief.com Interview with:
Oved Daniel MD
Headache and Facial Pain Clinic
Ramat-Aviv Medical Center
President of the Israeli Headache Association
Tel-Aviv, Israel

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

Response: Migraine patients experience disabling symptoms, which often left untreated or exasperated by currently available therapies, therefore, a significant unmet medical need for treating migraine pain remains.

Current external nerve stimulation devices only target one nerve and this study assessed the safety and performance of a new external nerve stimulation device that stimulates the two major nerve branches associate with pain (occipital and trigeminal) .

The Relivion MG is a non-invasive device that the patient can wear at home to treat their migraine pain and associate symptoms.

Preclinical Trial Tests Combination of CBD:THC for Migraine Relief

PainRelief.com Interview with:
Andrew F. Russo, Ph.D.
Professor, Dept. Molecular Physiology and Biophysics
University of Iowa
Iowa City, IA 52242

Dr. Russo

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

Response: The company Schedule 1 Therapeutics approached us with an interest in testing a combination of CBD:THC in migraine. We thought the topic had tremendous public interest so we teamed up with them and won grants from the Migraine Research Foundation and from the National Institute on Drug Abuse.  

Experimental Hydrogel Improved Chronic Pain from Degenerative Disc Disease

PainRelief.com Interview with:
Douglas P. Beall, MD, FSIR
Chief of Radiology Services
Clinical Radiology of Oklahoma

Dr. Bealll

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

Response: Degenerative disc disease (DDD) is the leading cause of chronic low back pain and one of the world’s most common medical conditions contributing to high medical and disability costs. Healthy spinal discs act aids spine movement and distributes force which allows for spine flexibility and even distribution of the load that is placed on the spine. Each has a firm outer layer and a soft, jelly-like core. With normal aging, discs tend to become dry, thin, cracked or torn, which can cause pain and abnormal motion.

Substances called hydrogels, with biochemical similarities to the intervertebral disc designed to augment both the core and outer layer, have been used for years to help repair degenerated discs. First-generation hydrogels are placed as a soft solid, through a surgical incision, but were not simple to place and had a tendency to migrate from where they were originally placed.

For a first-in-human trial, our team conducted a prospective, single-arm feasibility study to evaluate an experimental, injectable hydrogel for safety and performance in relieving chronic low back pain caused by DDD. We used a second-generation hydrogel (Hydrafil™) developed by ReGelTec, Inc.. Unlike earlier hydrogels, it can be temporarily modified into a liquid and injected rather than placed through a small incision. In 2020, this product received FDA’s breakthrough device designation, allowing expedited review based on promising early evidence.

We recruited 20 patients, aged 22 to 69, who each described their pain as four or higher on a zero to 10 scale. None had found more than mild relief from non-surgical management, which includes rest, analgesics, physical therapy, and back braces. Patients were sedated for the procedure, and the gel was heated to become a thick liquid. Guided by fluoroscopic imaging, an interventional radiologist used a 17-gauge needle to inject the gel directly into the affected disc(s). The gel filled in cracks and tears and adhered to the disc’s core and outer layer.