Researchers seek non-opioid alternatives to manage neuropathic pain

As the world reels from the opioid crisis, many wonder: Are novel non-opioid therapies on the horizon to better target pain’s root causes?

Is it too much to hope that neuropathic pain (NP) patients, which represent 7 per cent to 10 per cent of the general population, might find relief?

Neuropathic pain is a severe form of chronic pain that’s notoriously hard to treat primarily because of its complex pain biology.

NP patients, unfortunately, form an unwilling part of the opioid crisis, as nearly 70 per cent of peripheral neuropathy patients end up taking opioids, often chronically.

Mayo Clinic researchers also reported in 2021 that more patients with newly diagnosed diabetic neuropathy were prescribed opioids during the years spanning 2014 – 2018 than were prescribed guideline-recommended medications.

Research clearly shows patients’ search for pain relief, combined with an inadequate response from first line NP treatments, rather than opioid abuse, is the main factor driving NP patients’ role in the opioid crisis.

This is somewhat ironic, since opioids haven’t been particularly effective for neuropathic pain.

In addition, their addictive potential is especially risky for patients in the grip of unrelenting pain.

In an FDA report on neuropathic pain titled “The Voice of the Patient,” patients described their pain in terms such as “a blow torch on their body” or “a nail pounded into the same location over and over again.”

Such pain is felt “24/7,” in the words of one patient.

Overall, research shows that quality of life is more impaired in patients with chronic neuropathic pain than in those with chronic non-neuropathic pain that does not come from damaged or irritated nerves.

There is a clear need for better analgesics for NP patients because current treatments only go so far.

While pain treatments like anti-seizure drugs and tricyclic antidepressants are effective for some patients, millions of others fail to respond, or respond insufficiently. Current recommended treatments are effective in less than half of NP patients.

What’s more, in those patients who get some relief, current treatments are often associated with debilitating side effects, such as dizziness and fatigue, again resulting in treatment discontinuation.

The pain itself, but also the side effects from treatment, can impact all aspects of daily life, including sleep and mental health.

Progress in understanding the pathophysiology of neuropathic pain

Neuropathic pain develops from an injury or disease of the nervous system.

The experience of neuropathic pain is the result of a complex combination of increased stimulation of peripheral neurons, a heightened sensitization of such neurons, decrease in the threshold of those neurons to be stimulated, a decreased ability of neurons to return to a resting state, or a permanent change in the central modulation of the perception of the pain caused by these hypersensitized neurons.

Each of these steps is managed through a combination of (subtype) receptors and channels, and each step is inextricably linked to another.

In addition, depending on the nervous system damage from the inciting disease or injury, there can be variability in the altered pain messaging and in the modulation of it.

Finally, inflammatory pain and neuropathic pain, previously considered distinctly different pain types, can be both a cause and a result of each other and therefore may co-exist in a single neuropathic patient.

This understanding makes it clear that the treatment of a neuropathic pain patient needs to address multiple mechanisms to deliver a meaningful change in the pain perception of an individual patient.

Current and emerging therapies to treat neuropathic pain

Current first-line treatments for pain related to diabetes, HIV, chemotherapy, autoimmune disorders, and spinal cord injury (SCI), among other conditions, include: gabapentinoids, tricyclic antidepressants (TCAs), and selective serotonin-norepinephrine reuptake inhibitors.

Second-line and other non-opioid treatments include lidocaine and capsaicin for peripheral neuropathic pain and corticosteroids as an adjuvant analgesic. Interventional strategies include nerve blocks and neuromodulation.

Emerging therapies aim to treat mechanisms of NP, and not just its symptoms.

Such therapies, and promising applications, include:

• Noninvasive neuromodulation techniques, such as repetitive transcranial magnetic stimulation, approved for use in depression – being tested in phantom limb pain, diabetic neuropathy, and fibromyalgia.
• NMDA receptor antagonists such as memantine, approved to treat Alzheimer’s disease – being tested in complex regional pain syndrome, chemotherapy-induced pain, fibromyalgia, and phantom-limb pain.
• Cannabis-derived compounds – being used to treat pain associated with diabetes, multiple sclerosis, and chemotherapy. Sativex, approved in the UK, awaits FDA approval for treating spasticity in MS patients.

Novel compounds to treat neuropathic pain and epilepsy: iQure Pharma’s approach

Thanks to a deeper understanding of pain biology shaping the field, researchers like those at iQure Pharma are making great strides.

iQure Pharma researchers are testing novel compounds that help to modulate glutamate, an excitatory neurotransmitter that forms a key step in the pain signaling process.

Its overstimulation can lead to excitotoxicity—neurons becoming dysfunctional or die due to an excessive release of glutamate.

Henk de Wilde

This excessive release of glutamate is implicated in both neuropathic pain and epilepsy, as well as other degenerative diseases. iQ-007 stimulates the naturally occurring transporters to bring the excess glutamate back to normal levels.

In addition, another compound called iQ-008 works on sodium (Na+) and calcium (Ca2+) channels, and on the TRPV1/CB2 complex: key pathways involved in the development and maintenance of chronic pain.

iQure Pharma’s goal is to provide different approaches that can provide better therapeutics for neuropathic pain, to help the millions across the globe whose “excruciating pain is an inescapable reality of life,” as noted by global health lawyer and Georgetown University Law professor Allyn Taylor, J.D., LL.M, J.S.D.

iQure Pharma Inc. (iQure) is a Princeton-based global biotech company focused on developing novel treatments for neuropathic pain.

It’s been selected out of over 1100 companies to join the Endless Frontier Labs 2022-2023 program by the renowned Stern School of Business at New York University.

Research into one of its lead drug candidates, iQ-007 ((R)-AS-1), has been published in the Journal of Medicinal Chemistry, published by the American Chemical Society.

The research, Discovery of (R)-N-Benzyl-2-(2,5-dioxopyrrolidin-1-yl)propanamide [(R)-AS-1], a Novel Orally Bioavailable EAAT2 Modulator with Drug-like Properties and Potent Antiseizure Activity In Vivo, discusses iQ-007’s unique mechanism of action and suggests iQ-007 as a First-in-Class EAAT2 Positive Allosteric Modulator (PAM).

Pain looms as a “global health priority” due to its prevalence, as well as its disproportionate impact on women and the economically challenged.

With continuing research and support, scientists are working toward better therapies for the unrelenting pain that, according to World Health Survey data from 52 countries, affects roughly 27.5 per cent of adults age 25 and older.

Helping people to become pain-free is increasingly becoming a social and economic necessity.

Henk de Wilde is co-founder, COO and R&D Director at iQure Pharma Inc.

A pharmacist by training, Henk began his career as a Project Leader at Pharma Bio-Research B.V., (acquired by PRA in 2006), a Phase I Clinical Research Organisation.

In several senior management positions, he helped grow the company to be one of the largest Phase I units in the world. Henk then joined Roche as Clinical Project Leader and worked several years in Clinical Development.

 Since leaving Roche in 2017, Henk has been involved in the successful launch of three companies in venture capital, IT, and business process optimization for life science.

In 2018, he joined Widler & Schiemann as Managing Director Europe supporting small and midsize pharma and biotech companies in the development of new medications.

You can connect with Henk on LinkedIn.