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19 Articles in Volume 20, Issue #4
20/20 with Dr. Nathaniel Katz: Pain Research and Future Therapeutics
A 20-Year Timeline: Pain Therapeutics and Regulations
A Comparison of the Alpha-2-Adrenergic Receptor Agonists for Managing Opioid Withdrawal
A Pain Assessment Primer
After the Task Force: A Conversation with Vanila A. Singh, MD
Ask the PharmD: Can opioids and benzodiazepines ever be used together?
Cognitive Strategies and Mindful Awareness for Integrative Pain Care
COVID: Clinical Considerations for Acute and Post-Infection Symptoms
Editorial: Fudin and Gudin Tackle Pain Care History – Asking, Have We Done a 180?
From Hands-On to Home-Based Care: Physical Therapy Undergoes a Paradigm Shift Due to Pandemic
MS-Related Pain and Spasticity: Are Cannabinoids an Option?
New Biological Agents for Psoriatic Arthritis: A Monoclonal Antibody Primer
Pandemic Presents Unexpected Opportunity to Embrace Multimodal Analgesia and the Integrative Care Team
Provider Perspective on Knee OA: Injections and RFA Options
Redefining the “Pain Specialist” of Today
Resident’s Corner: Climbing the Learning Curve in Pain Management
The Evolution of Pain Management: Experts Weigh In
Tips from the Field: How to Enhance Practice Efficiency
Tumor Necrosis Factor (TNF) Inhibitors: A Clinical Primer

20/20 with Dr. Nathaniel Katz: Pain Research and Future Therapeutics

A conversation on scientific research, the use of patients as measurement instruments, and why we need to remember the history of opioid use and the purpose of rational management to make real progress.

This discussion is part of a new conversation series led by Editors-at-Large Jeff Gudin, MD, and Jeffrey Fudin, PharmD, in honor of PPM’s 20th anniversary of publication. A condensed transcript follows. Access the audio file, which includes more detail on Dr. Katz’s collaboration with FDA and how he models an effective clinical trial.


Dr. Gudin: Nat, tell us about your journey into pain management.

Dr. Katz: I actually started in engineering school and then went to medical school. I never thought engineering would be relevant again, but as it turns out, I have relived that experience with my work in clinical trials. I did a residency in neurology and went right into pain management because so much of what I saw in neurology had to do with chronic pain, and I wanted to help manage those patients.

It didn’t take me long to figure out that the treatments we have for chronic pain just don’t cut it for most patients. That set me in the direction of setting up a clinical trial center and figuring out how to do better clinical trials.

Along the way, I had the opportunity to chair an FDA advisory committee which was one of the most professionally satisfying things that I’ve ever done – I encourage anyone who has the opportunity to collaborate with the FDA to do so. It’s been an exciting journey.


Dr. Fudin: Can you dig into some of the problems with clinical research methodology that you observed and what led you into that space?

Dr. Katz: So I’m sitting there in the trenches like you guys in the in the mid-1990s, maybe 5 years into my clinical practice, and it started to dawn on me that I didn’t want to dole out the same treatments for the next 40 or 50 years. I wasn’t a basic scientist so I started to ask, ‘What am I going to do to accelerate the development of new therapeutics?’ I wasn’t about to start a preclinical scientist or chemist career at that stage of my life so I thought, I’ll do clinical trials.

Soon, pharmaceutical companies were coming to me asking why their clinical trial had ‘failed.’ I thought, what does failure even mean in the context of a trial? They might have been studying morphine or ibuprofen, or another effective treatment, and failed to separate drug from placebo.

The real question was, why did that happen? I had always thought that you give the drug to the patients and if it works, then it beats placebo. I had no idea how wrong and naive that notion was at the time. I now know that a trial has to be finely calibrated and tuned to get an accurate readout of the effectiveness of a drug. A clinical trial is a measurement instrument just like a spectrophotometer or a weighing scale – you want to know how much you weigh; well you have to be sure all the little gizmos in your scale are calibrated. And if they’re not, you won’t get an accurate weight. It’s the same with a clinical trial.

Around this time, my engineering background kicked in and a light bulb went off in my head that thinking about clinical trials as a collection of patient experiences is inadequate, and we have to instead think of a clinical trial as a finicky measurement instrument requiring constant calibration. That realization set me off on a now 20-plus year career trying to figure out how to do that.


Dr. Fudin: We recently wrote about flawed assessment measures in a PPM editorial, begging the question, why are there not more breakthrough analgesics? There has been a lack of good trials looking at things other than opioids over the years. So with that in mind, where do we need to go to improve clinical trials as a tool to develop new therapeutics?

Dr. Katz: Well, there are a few distinct advances that have just begun but need to be consolidated. First, we need a paradigm shift in how we think about clinical trials – which may be hard to swallow for both clinicians and patients because we all have the notion that clinical trials are about aggregating the patient experience and figuring out how the patients did. Clinical trials for the purpose of developing new therapeutics are not for that, they are for characterizing the drug or treatment or device.

Essentially, we are using patients as instruments to characterize aspects of new treatments. We ask, how much does the drug relieve pain and how much does it reduce sleep? But how do we measure how much something reduces pain? We see the patient as not only a human being whose benefit we care about, but in their role as a clinical trial participant, as a measurement instrument.

For some reason, we understand this when it comes to pharmacokinetic (pK) trials. If we have to get the half-life of a drug, we get 25 volunteers, we take their blood every 10 seconds, and out pops the C-max of the drug and we forget about the patients.

But when it comes to efficacy or safety of a drug, somehow, we can’t get the patients out of our mind. We think that they’re the goal.

In some cases that may be true, but really, the purpose of a clinical trial is to characterize the treatment, not the patients, and to do so, we have to calibrate the patients as a measurement instrument and not simply say, ‘the patient says the pain is a 10 out of 10.’ That’s not that helpful. Studies have shown that one-third of patients with chronic pain cannot report their pain accurately. We cannot accept that. We need methods to help patients report their symptoms more precisely. 


Dr. Gudin: This is absolutely fascinating and the subjective nature of a treatment, as you say Dr. Katz, is so important to be able to characterize. When you throw in the placebo response and the patient relationship with the clinician, those factors can either help or kill a trial. It’s a real challenge.

Let’s chat a bit more about your legacy in building this specialty we call ‘pain medicine.’ I think the three of us will agree that opioids are a tainted part of our history. I recently heard you tell a story about the history of opioids and how we may be repeating ourselves – could you give us a snapshot?

Dr. Katz: We all know we know that the word ‘opium’ comes from the Greek word meaning ‘juice’ and there is archaeological evidence from caves in Europe of people using small curved cups and curve blades to incise the seed head of the opium poppy to get that juice. So, thousands of years before our modern scientific enterprise, herbalists figured out that opioids work for pain.

The modern story begins in the mid-19th century where, after the Civil War in this country, you have legions of veterans who were severely traumatized – both physically and psychologically. At the same time, we had the crystallization of morphine, which was actually the first alkaloid medicine from a plant ever crystallized, and then, we had the third element in that perfect storm – which was the invention of the hypodermic needle in 1850. People started to inject these veterans and other people with opioids as a maintenance treatment. Before you knew it, 1 in 200 people in this country were estimated to be addicted to morphine, which is not far off from today’s opioid addiction rate – and that practice turned into the first prescription opioid crisis.

Since then, physicians in their zeal to help patients completely forgot about the history of opioids as being two-faced – they heal and they harm. It took the government another 50 years to take action, via the Harrison Narcotics Tax Act [signed into law in 1915, the Act regulated and taxed the production, importation, and distribution of opiates and coca products].

The resulting opioid drought lasted for probably another half-century until the 1970s, when we saw the rise of patient care, palliative care, and the patient rights movement – and again, we forgot again about the risks of opioids. Now, you can hardly avoid the crisis and we are forgetting about their benefits.

I’ve struggled mightily to establish a scientific basis for a middle ground that recognizes that opioids are helpful but we have to recognize there’s a scientific basis for their benefit and for their harm.


Dr. Fudin: We are seeing similar trends with cannabinoids, kratom, and other natural substances today, so let’s talk about why prescribers need to be familiar with risk-mitigation strategies for opioids and any drugs for that matter.

Dr. Katz: I was proud to participate in a lot of the foundational work around urine drug testing and prescription drug monitoring programs. And while those tools are far from perfect, as we enter the future of rational opioid management and rational management of our other therapeutics, clinicians need to realize that they have more tools than they had before to better understand their individual patients.

I foresee that we’re going to exchange an opioid crisis for a cannabinoid crisis because – as you noted – we are once again forgetting about the risks. But I do think the future of pain management is very interesting, and I see it progressing on two fronts.

One is the better use of the tools that we currently have in our toolbox and the second is the development of better tools. But to use both, we need to come to a more rational place about the use of opioids and cannabinoids.

We also need to recognize the use of nonpharmacologic therapeutics in pain management. In pain fellowship, we all learn about multidisciplinary pain management, rehabilitation, physical therapy, exercise, yoga and psychological treatments. But in practice, because of insurance reimbursement issues and other pragmatic problems, we have in many cases not been able to provide integrative care to our patients. Yet, we all learn in the trenches that integrative care gives the best results.

So I think we need a wholesale change to reimbursement practices and to patient access in primary care to these multidisciplinary treatments to achieve the best outcomes.

People who write guidelines also need to remember the stories – because sometimes guidelines are political documents as well and, unfortunately, are often written more with the media in mind than patient welfare.


Dr. Gudin: What else would you like to see in the years ahead?

Dr. Katz: In terms of new therapeutics, we need to sharpen our tools for clinical trials and remember that trials are a measurement instrument. We need to develop ways of knowing whether clinical trials are actually measuring our treatment effects accurately or not. And we need to view former ways of conducting trials as intolerable. Just like practice needs to be scientifically based, research methodology needs to be scientifically based as well.

The opening of a scientific research paradigm will require us to accelerate the development of new therapeutics, which have unfortunately not been that successful in the decades that I’ve been involved – but it’s happening, and we have a bright future with a better clinical research methodology ahead of us.


Dr. Nathaniel KatzDr. Nathaniel Katz

Nathanial Katz, MD, is a neurologist and pain management specialist. He currently serves as Chief Scientific Officer of Analgesic Solutions, which he founded in 2006 with the mission of modernizing the design and conduct of pain clinical trials to advance the “scientific quality” of pain clinical research, and to empower effective treatments for patients. Dr. Katz previously founded the Pain & Symptom Management Program at Dana Farber Cancer Institute and the Pain Trials Center (a clinical analgesics research unit) at Brigham & Women’s Hospital, both of which he directed until 2001. From 2000 to 2004, he served as chair of the FDA’s Advisory Committee on Anesthesia, Critical Care and Addiction Products. Dr. Katz completed his neurology residency at Tufts-New England Medical Center (where he now serves as an adjunct associate professor of anesthesia) and his pain management fellowship at Brigham & Women’s Hospital. He also holds a master’s degree in biostatistics from Columbia University.


Throughout 2020, we will be featuring more dialogues on the evolution of pain management over the past two decades and what the future may hold. To get involved, email the editorial team. See Episode 1 with Lynn Webster, MD, Episode 2 with Peter Staats, MD, and Episode 3 with Suzanne Amato Nesbit, PharmD and Episode 5 with Drs. Carmen R.Green and Johnathan Goree and Mark Wallace, MD.
Last updated on: November 16, 2020
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