The opioid epidemic remains unrelenting, wreaking havoc and causing heartbreak for countless families across the US. But this story is one that spans decades, etched with alarming statistics that grow more devastating with each passing year.

For example, in just one decade, from 1999 to 2019, the overdose death rate increased by over 250%, and in 2020, with the COVID-19 pandemic acting as a catalyst, drug overdose deaths surged again by another 30%.

Fast forward to today, in 2023, we’re faced with another unsettling reality: drug overdose deaths in the US have reached a staggering 108,407 – one of the highest numbers ever recorded and a stark reminder that the battle against opioid addiction is far from won.

As the opioid crisis continues to evolve, there’s no denying that an overreliance on prescription opioids for chronic pain management has contributed to the situation.

That’s because opioids, while effective at dulling pain, can be highly addictive. In fact, in the last 20 years, prescription opioid deaths have increased fivefold. Yet, at the time, millions of Americans do not have adequate relief for persistent pain, meaning there’s a real urgent patient need for alternative non-addictive therapies for pain management. 

Enter Life Sciences.

Life Scientists understand this is a problem that demands a fresh approach, and so, they’re on a mission to find non-addictive alternatives for pain management, focusing on reducing risk, removing barriers, and, most importantly, saving millions of lives. 

In this blog post, we’ll explore the effects of opioids on the human body, delve into the FDA’s initiative to foster the development of alternative pain medications and uncover the groundbreaking developments unfolding throughout the world of Life Sciences for new pain management therapies.

What Are Opioids?

Opioids are a class of drugs that includes the likes of heroin along with prescription pain relievers such as oxycodone, hydrocodone, codeine, morphine and fentanyl, which have a unique impact on the body.

These drugs, when ingested, activate opioid receptors in the brain and nervous system, which effectively blocks pain signals. At the same time, opioids also induce a sense of euphoria, and those feelings of being ‘high’ can lead to addiction.

 See, the challenge with opioids is that they broadly influence primary binding sites in the body, meaning their effect can extend beyond pain relief and seep into other physiological processes, resulting in unwanted and potentially dangerous side effects.

 Currently, chronic and inflammatory pain is often treated with opioids. Even when prescribed appropriately, they pose a high risk of leading to opioid dependence, increasing the likelihood of overdose. Hence, there’s a pressing need to develop more effective and safer pain management medications for acute pain patients.

How Is the FDA Supporting The R&D of Non-Addictive Pain Medication?

The severity of the ongoing opioid crisis is not slowing down. The FDA has noted this as a serious public health crisis and, for that reason, launched a new initiative to promote the development of non-addictive pain medications to manage persistent pain, reduce contact with opioids and prevent the cycle of addiction.

As part of this initiative, the FDA has published an updated draft guidance, providing recommendations to Life Sciences organizations to help navigate the common challenges encountered when developing non-addictive treatments specifically tailored for managing acute pain lasting up to 30 days.

The guidance supports the HHS Overdose Prevention Strategy, which focuses on four key pillars: primary prevention, harm reduction, evidence-based treatment and recovery support.

The document also outlines the FDA’s three key ideas concerning the development of non-opioid analgesic drugs for acute pain:

-      Types of Drug Development Programs: The FDA offers guidance on appropriate drug development programs for generating the necessary data to effectively manage chronic pain without resorting to opioids.

-      Use of Claims in Labelling: The document explores the potential use of claims in labelling that relate to the reduction or elimination of opioid use, outlining the requisite data to support these claims.

-      Expedited Programs: The guidance addresses the potential use of the FDA’s expedited programs to support the development of non-addictive pain management solutions, accelerating the availability of safer alternatives.  

 The draft guidance also fulfils the legal mandates of the SUPPORT Act, which directs the FDA to issue new or update existing guidelines to help address the specific challenges associated with developing non-addictive treatments for pain management.

Where is R&D at In Regard to Non-Opioid Alternatives?

1.    UC Davis Team Creating Monoclonal Antibodies to Fight Acute Pain

Monoclonal antibodies, which are artificially created in a lab, have already demonstrated their versatility in the world of medicine. The FDA has previously granted approval for monoclonal antibodies to treat and prevent migraines, and they played a crucial role throughout the COVID-19 pandemic, with physicians administering infusions of monoclonal antibodies to help patients fight the virus.

Then, in early 2022, a dedicated team of researchers at UC Davis received a $1.5 million grant from the National Institutes of Health’s (NIH) HEAL initiative to ramp up scientific solutions to combat the ongoing national opioid crisis.

The team got to work on developing a monthly non-addictive pain treatment that will replace high-risk, highly addictive opioids. To do so, the team are focusing on specific ion channels within nerve cells, known as voltage-gated sodium channels. These channels are key transmitters of pain, akin to ‘pores’ on the surface of nerve cells.

The researchers at UC Davis are focusing on three specific ion channels in particular (NaV1.7, NaV1.8 and NaV1.9), and they plan on creating monoclonal antibodies designed to seamlessly slot into these channels. The anticipated outcome is that the antibodies will prevent the channels from sending pain signals without interfering with other signals sent through the nerve cells.

To help them on their mission, the team are working with two software programs: Rosetta and AlphaFold. Rosetta facilitates the design of intricate virtual models of proteins, allowing for an in-depth analysis to determine which proteins are the most suitable candidates to target the desired ion channels. AlphaFold then validates the accuracy and reliability of the proteins designed by Rosetta.

Once a roster of promising proteins has been identified, the team will then create the antibodies, which will undergo initial testing on lab-created tissue. The idea is that the monoclonal antibodies will circulate in the bloodstream for over a month before the body naturally breaks them down.

That means that these circulating antibodies will be able to provide sustained pain relief for weeks at a time, rather than current pain medications that need to be ingested daily and run the risk of addiction. 

2.    Washington University School of Medicine Identifying Potential Pain Relief That Doesn’t Trigger Addiction or Hallucinations

For years, Life Scientists have been on a journey to create pain-relieving drugs that selectively activate one type of opioid receptor, known as the kappa opioid receptor. The reason being is that unlike its notorious counterpart, the mu opioid receptor, the kappa receptor is not linked to addiction.

However, here’s the catch… Many attempts to develop drugs focused solely on the kappa receptor have hit a roadblock. While these compounds effectively relieve pain, they often bring along another unwanted side effect: hallucinations.

Now, thanks to a study by the Washington University School of Medicine, another potential pathway to pain relief that neither triggers addiction nor hallucinations has been unveiled.

Using electron microscopes, the team of researchers uncovered how a natural compound related to the salvia plant selectively binds to the kappa receptor, which then activates hallucinogenic pathways.

This discovery opens the door to the development of new drugs that target alternative kappa receptor binding sites that could relieve pain without triggering addiction or hallucinations – an incredibly important breakthrough in pain management medicine.

Moving forward with their developments, the team have discovered a class of seven different signalling proteins known as G proteins. Each of these proteins causes the kappa receptor to activate several different pathways, and although similar to one another, the distinct differences could help explain why some compounds cause side effects like hallucinations and why others could avoid this reaction altogether.

The team is now investigating how these different G proteins interact with the kappa receptor. Once they’re able to distinguish their different activation points, they’ll then develop ways to stimulate the receptor without provoking hallucinations, hopefully ending up with a non-addictive painkiller devoid of dangerous side effects.

Tao Che, principal investigator and assistant professor of anaesthesiology says of their breakthrough, “We have found that the hallucinogenic drugs can preferentially activate one specific G protein but not other, related G proteins, suggesting that beneficial effects such as pain relief can be separated from side effects such as hallucinations. We expect it will be possible to find therapeutics that activate the kappa receptor to kill pain without also activating the specific pathway that causes hallucinations.” 

3.    Purdue College of Pharmacy Developing a New Non-Addictive Class of Compounds

Purdue’s College of Pharmacy (worth noting, not in any way associated with the ill-reputed Purdue Pharma) has developed a new non-addictive class of compounds that could hold the key to new pain management therapies to help combat opioid addiction and overdoses; two critical components contributing to the nation’s opioid crisis.

The compounds in question are the brainchild of Val Watts, professor of medicinal chemistry and molecular pharmacology and associate dean for research at Purdue’s College of Pharmacy, and his team. What makes this series of compounds so remarkable is that they completely bypass opioid receptors, acting directly on AC1, which blocks pain triggers. 

While these novel compounds have the potential to treat pain and reduce dangerous side effects, like dependence and addiction, there are also indications that they could play a role in alleviating the signs and symptoms of opioid withdrawal.

Val Watts is optimistic about the impact of this discovery, stating, “This could be the drug of choice for chronic pain, so physicians wouldn’t have to prescribe opioids long-term, and we would be less likely to see dependence and addiction.”

4.    Indiana University’s Pre-Clinical Study Finding PAMs Enhance the Effect of Natural Pain Relief Chemicals  

With the opioid crisis reaching epidemic proportions in recent years, Indiana University scientists have reported a hopeful path toward pain relief that sidesteps addictive side effects.

In their pre-clinical study, the team uncovered that positive allosteric modulators (PAMs) enhance the effect of pain relief chemicals naturally produced by the body in response to injury or stress. Notably, they achieve this without creating tolerance or decreased effectiveness over time – factors contributing to addiction in patients who use opioid-based pain medications. 

That’s because PAMs target secondary drug receptor sites in the body, acting as amplifiers for the brain’s intrinsic painkillers. In doing so, they selectively influence the body’s biological processes, effectively dampening the sensation of pain.

In this study, the spotlight was on the PAM strengthening two endocannabinoids, acting upon the CB1 receptor that responds to THC. It was found to enhance the effects of the endocannabinoids (chemical compounds released by the human body in response to pain) without introducing unwanted side effects commonly associated with cannabis use, such as impaired motor functions or lowered body temperature.

What’s truly intriguing is that the pain relief offered by PAMs was stronger and longer-lasting than drugs that block an enzyme that breaks down and metabolizes the brain’s own cannabis-like compounds. Unlike these drugs, which interact with every receptor site throughout the body, PAMs act like precision instruments, directing natural painkillers to the right place in the brain at the right time. 

Throughout their study, the IU research team also put other pain-relief compounds to the test, including a synthetic cannabinoid and a metabolic inhibitor. The results were clear: PAMs presented the strongest advantages, with other compounds more likely to trigger addiction or diminish effectiveness over time – a major step forward in the search for non-addictive pain relief alternatives.

Conclusion 

The devastating toll of opioid misuse and abuse has cast a long shadow over society, leading to far too many overdose deaths. Still, the silent and persistent burden of chronic pain impacts over 100 million adults and costs between $560 to $635 billion (far surpassing the costs of the six most costly major diagnoses). With sobering statistics like these only growing, the need for safer and more effective pain-relieving medications becomes all too apparent.

Fortunately, as demonstrated above, with support from the FDA, research and development into non-addictive analgesics for acute pain is progressive and promising. These advancements only provide us with a glimmer of hope, pointing toward a future where chronic pain can be managed effectively without the risks associated with opioid use looming overhead.

Want to learn more about the opioid crisis? We recommend adding Dopesick, Painkiller or The Pharmacist to your ‘to watch’ list. These eye-opening and educational narratives provide valuable insights into the origins of the opioid crisis, serving as poignant reminders of the work that lies ahead.