Ketamine: A Paradigm Shift In Pain Management

Between 1999 and 2018, nearly 450,000 people died from an opioid overdose, per the CDC. Almost 70% of the 67,367 drug overdose deaths in 2017 involved an opioid. Is this shocking to you? It’s shocking to me. I knew it was bad—we all understand the looming threat of the opioid epidemic—but I had no idea it was this bad. My name is Nathan Graves. I write content for Ketamine News and Ketamine Media. Why is this relevant? I work directly in the healthcare industry.

You may think that all healthcare-related jobs are doctors, nurses, or pharmacists, but there are millions of other people who work jobs in this industry that don’t require years of medical school. What this means is that, while I’m no doctor or nurse and am not nearly as qualified as these experts to speak on these topics, I’m at least fairly well-read and well-educated.

So why is it that these statements are such a shock to me? Is it really possible that the opioid epidemic is worse than any of us feared?

Maybe not. Maybe you already understood just how far-reaching this crisis is.

At any rate, the question should stop being “how can it be this bad?” and should instead become “what can we do about it?” Everyone has their own theories. Like any hotly-debated topic, there’s a whole lot of opinions, a whole lot of misinformation, and a great variety of emotions held on both sides. 

Groups like Bexson Biomedical are actively searching for new solutions—or rather, old solutions examined under a new light. Chances are if you’re reading this you’re at least a little familiar with ketamine. But if you’re not, I’ll back up a second and give you some background.

“Ketamine actively blocks a receptor that is involved in the fundamental process of memory formation,” explained Dr. Jeffrey Becker, Chief Scientific Officer at Bexson Biomedical. He then further detailed to me how ketamine is responsible for the rapid treatment of chronic pain.

Ketamine’s potency in pain management has been shown to be equal to or better than a vast number of strong opiod and opiate medications, including methadone.

“We use the term ‘long term potentiation’, meaning that when this one receptor—the NMDA receptor— is activated, connections can be strengthened or ‘potentiated’. This is what allows neuronal responses to change over time, learning per se. In pain signaling there is a learned component that drives the response to injury, and this process can continue, maintaining itself beyond what is required for us to protect the injured area. This is especially true of chronic pain, where pain circuits can become so strengthened that they continue on firing even when the injury is healed and gone.”

So we know ketamine is a powerful pain reliever, but can it possibly compare to medical opioids?

“Absolutely. Ketamine’s potency in pain management has been shown to be equal to or better than a vast number of strong opioid and opiate medications, including methadone, meperidine, fentanyl, and even the most recognizeable – morphine. 

Ketamine can additionally be used safely in conjunction with opioid medications, so it doesn’t have to be a situation of ‘either/or.’ Ketamine has distinct properties that allow a reliable reduction of total opioid dosing in pain management. In addition, chronic pain status will generally improve with ketamine treatment over time rather than worsening, as is often seen with opioid medications, due to its capacity to block the development of hyperalgesia, a process which converts acute pain into a difficult chronic condition.”

When presented with the evidence for ketamine as a treatment option, it’s almost impossible not to start connecting the dots. If it’s clear that more efficient and less dangerous substances exist to treat the same conditions we’re using opioids to treat right now, why are we prescribing so many opioids? To answer this, let’s take one of the most notorious prescription opioids for example: Fentanyl. In 2017, there were more than 1.7 million prescriptions of this drug in the United States alone. Why is that? 

Fentanyl is a synthetic opioid that can be 50 to 100 times more potent than its predecessor, morphine. It’s cheaper than drugs like heroin, paradoxically, despite being so much more potent. Simply put, insurance companies are a business. Not that all insurance companies are inherently greedy or evil, but the point of a business is to generate revenue. Insurance companies are going to go with the cheaper and more readily available treatment options. Furthermore, the use of ketamine for pain treatment is occuring, but it is not widely accepted by insurance companies. “Actually,” continued Dr. Becker, “ketamine is already a tool used by many innovative pain management doctors in multiple ways. In-office infusion procedures can be helpful for high-grade pain and stopping a serious pain crisis. Lower doses of ketamine taken at home are sometimes offered as well, to extend the benefits of these office procedures or to utilize ketamine’s anti-tolerance and opioid-sparing effects. 

There are a number of problems that have slowed innovation though. First, ketamine is very poorly available by oral, sublingual, and intranasal routes of administration, and even when these routes would be a reasonable approach they are markedly inconsistent. Second, ketamine has a very short half-life, so the anti-pain effects can fade quickly. An approach that allows for production of steady-state plasma levels, even if very low, has been elusive. Currently, this effect can only be achieved by intravenous delivery inside the clinic or hospital. Finally, even where there is a potential value in the product development there can be difficulty in patent protection, which destroys any real justification for development.” The favoring of opioid treatments instead of potentially safer treatments like ketamine may not be the result of a massive money-making conspiracy, but may actually be more of a formality at this point in time as the available treatment becomes more widely accepted and tested.

“Many opioids and opiate medications are FDA approved for pain management, available in multiple delivery methods to solve the various problems in clinical use and application. Immediate release and extended-release pills, transdermal patches, and sublingual formulations are all approved and readily available. And, doctors are generally already trained in their use. 

None of this is the case with ketamine. All home use of ketamine is essentially off-label and is only available through small compounding pharmacy services engaged in uniquely for each patient. Despite this, even more pain specialists are opting for the office-based ketamine infusions for pain management and compound products for home use

The key opinion leaders we have discussed our program [with] are very pleased to anticipate the availability of an approved ketamine product and delivery system with high bioavailability, ease of use, and dosing consistency. They have been very clear that this will solve many of the problems they encounter in human pain management of various etiologies.”

Though ketamine itself is considered a safe drug—it’s even high on the World Health Organization’s Essential Medicines List—the application of this compound has shifted greatly over the last few decades.

“Awareness of ketamine’s potential in treating human disease, pain, and health conditions has expanded to encompass a substantially wider range of physicians. Innovative high-quality research, drug development programs, the consciousness medicine movement, and patient advocacy have made more doctors informed about ketamine’s novel benefits.

As such, clinicians who may never have considered this drug or this mode of action in a therapeutic are being exposed to these ideas and new ways of considering the pathophysiology underlying some medical conditions.

In any complex field, when a new tool becomes readily available to solve long-standing problems in a new and efficient manner, there is reassessment of the underlying premises regarding the nature of the problem itself. This is especially true regarding ketamine and its potential in the treatment of pain and mental health indications.

Not only have we discovered an entirely new way of intervening upon pathophysiologic patterning, we are now starting to understand the long term benefits of early intervention and prophylaxis in treatment of devastating conditions such as post-traumatic stress disorder and acute pain crisis.  

We still have a lot to learn, and there is inevitably the potential danger of over-application of a dynamic new tool, but physicians are encountering a paradigm shift that will hopefully help bring new effective treatments where there have been gaps.” Dr. Becker further detailed to me how Bexson is assembling an impressive team, with areas of expertise in everything from the treatment of chronic pain and PTSD to the role of the NMDA receptors.

“We are very honored to have people with such expertise and heart join our program. We are still in start-up mode, and we have been fortunate to find immensely talented, competent, and mission-driven people to pull together the different components of this program. It helps that we are trying to solve the opioid crisis, which takes more lives each year than many historic wars, and that we are laser-focused on running an effective regulatory strategy and proper IND preparation. 

To start, my co-founder, Gregg Petersen, has deep expertise in drug development programs. I have almost 20 years of clinical experience and deep research into NMDA receptor pharmacology and clinical relevance in depression, pain, traumatic brain injury, and schizophrenia. Once we laid out our mission, we found people were excited to join us and help. It has been a truly amazing experience to witness ideas on paper become a reality with their help. Our novel subcutaneous formulation was led by Jason Wallach, Ph.D., who is an absolute genius regarding medicinal chemistry and the NMDA receptor pharmacology. He literally ‘writes the books.’ 

Our Advisory Board and Board of Directors is blessed by highly trained and experienced MD experts and entrepreneurs with deep experience in ketamine use, pump development, and drug program strategies. There are way too many talented people to mention individually here, but we were recently pleased to announce that Bill Carson, MD–previous CEO of Otsuka Pharmaceutical—joined us soon after his initial retirement. His insights are born from notable previous pharma success stories and have been very valuable to us. We feel confident that this team can take us forward, both with our lead indications of postoperative pains, but also staging Bexson for new potential programs when we finish initial Phase I trials, exploring other pain disorders and mental health conditions, such as PTSD, major depression and anorexia.”   

With teams like Bexson Biomedical making new strides in new treatment options like this, the future of pain management is beginning to look brighter than ever before. Can ketamine outright replace the need for opioids? Evidence indicates that they may well be able to.

In a short period of time, their team has been making great strides. “[On] February 1, 2019, Bexson was granted orphan-drug designation pursuant to section 526 of the Federal Food, Drug, and Cosmetic Act of ketamine for treatment of complex regional pain syndrome, covering the active moiety or the principal structural features of the drug (Orphan Drug Designation: DRU-2018-6693). This application was then based upon a large existing research literature supporting the use of ketamine to control or arrest the devastating pain associated with this rare disorder.

For many of our patients with CRPS, ketamine infusions can be the most important tool and at-home use with compounded ketamine products is common. We hope to make this at-home aspect of our care more successful with our subcutaneous delivery system, which should have notably superior bioavailability, and dosing consistency and control in comparison to oral and intranasal products. This chronic, high-grade pain indication is a good example of ketamine’s substantial potential and product gaps in pain management, but ketamine has shown efficacy in a wide variety of pain etiologies.

Once our patent strategy and filings matured, we turned to post-operative pain management as our lead type indication. This acute pain type has been very responsive to ketamine in research studies, and it represents a very large market to establish our product and raise revenue. It is also an indication that can maximize the social and health economic benefits of our technology. Post-operative pain management is a very common gateway to opioid addiction, with an estimated 160,000 Americans becoming dependent on, abusing or misusing opioids each year after surgeries. We hope to provide a powerful new solution to this deadly crisis, and produce revenue needed to expand research into other pain and mental health applications. We are designing our technology to be modular in this regard.”

The research at Bexson Biomedical aims to correct some of the very few drawbacks of ketamine infusion treatment: difficult to attain delivery methods and a short half-life. “Our new delivery system will capture all of the advantages of IV route of administration for the treatments outside of the hospital, increasing safe access to this vital medication for difficult conditions. This is a real game-changer because the key to unlocking ketamine’s true potential is highly controlled delivery via a route with high bioavailability. This isn’t  possible without any compounded products currently being prepared for patients to use in the home or in the office for ketamine assisted psychotherapy.

Even the mass approved intranasal esketamine can very notably vary in effects, both between patients and between separate visits in the same patient. The delivery technique and the general environment of the nasal cavity and nasal mucosa are important variables that make this route of administration somewhat unwieldy. The small, wearable patch pumps—so common in the insulin market—solve this problem handily, and patient satisfaction with their usability makes our case. Pain is a very motivating symptom and we have received very positive feedback from patients and key opinion leaders in pain management regarding the potential value of our products. 

The biggest pharmacokinetic issue that specifically limits application of ketamine in pain—namely, its short half-life—is solved via the pump delivery program, which can be shifted for different use cases and indications. This is why we are discussing this as a delivery system, as opposed to a single product. It should be quite dynamic.”

With teams like Bexson Biomedical making new strides in new treatment options like this, the future of pain management is beginning to look brighter than ever before. Can ketamine outright replace the need for opioids? Evidence indicates that they may well be able to. But the mere fact that it shows so much promise indicates that our society’s reliance on opioids may not be as inescapable as some had feared.


About Author /

Writer, illustrator, musician. Since being diagnosed with OCD, Nathan has infused within all his work the same chief objective: destigmatize mental health and the treatment of it.

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