In the US, there is currently an opioid crisis. Dr. John Streicher speaks to AZoLifeSciences about how we can improve opioid drugs to make them safer and more effective.
What provoked your research into opioids?
Opioids are really interesting. I first encountered opioids during my postdoctoral fellowship.
I was working with a scientist named Laura Bohn at the Scripps Research Institute, and she was an opioid scientist. I had not researched opioids previously, and as I got into it, I really found it a fascinating field and a field where you could really potentially do a lot of good because, in the United States, we have a severe opioid abuse and overdose crisis.
It is not nearly as bad in the UK and in Europe, but in the United States, we have about 40,000 people dying per year from overdose. We have many more who are addicted, and, at the same time, we have an enormous chronic pain population, so we need these drugs.
Therefore, you have these needs that are fighting each other, and a lot of people that are suffering and a lot of people that need help. Therefore, there is a great humanitarian aspect to it that I am enjoying.
At the same time, scientifically, I find the system very interesting. What is also appealing to me, as a scientist, is there is a lot of fairly simple behavioral tools that we can use.
It is pretty easy to study opioids and pain, where it is not so easy for other fields. We can look at the molecular level like we have done in this study, making changes at the molecular level, which have fairly simple behavioral outputs that we can use in order to see what those molecules are doing.
We can then translate that molecule into whole animal behavior, which in my mind is fascinating and is one of the strengths of this field.
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Why is it important to research the effects of opioids?
In our country, we have a hundred million people in some kind of chronic pain, and we are always trying to find alternatives to opioids.
Of course, something simple such as ibuprofen, acetaminophen, those drugs, or if your pain gets a little more severe, you take a tricyclic antidepressant, and of course, where possible, you try to avoid drugs.
I am a pain drug scientists, but I think there is great promise in approaches like exercise and even things like art therapy or equine therapy has been really helpful to people in chronic pain.
However, you are always going to have millions of people at the end of the day in which the other stuff is not working, and to get any kind of pain relief, they have got to have some kind of opioid drug.
Therefore, we have this need. We have to have a lot of people that need to take opioids in order to have some kind of quality of life and control their pain. But that is, of course, not the end of the story.
A certain number of those patients are going to become addicted to their medications and potentially go down an abuse pathway where they are putting their lives in danger of overdose.
Then, in addition, you have non-chronic pain patients, people that are just taking these drugs recreationally that go down the same path.
The opioids also have a host of negative side effects. Apart from addiction, you have constipation (which is severe), tolerance, somnolence, mental clouding, nausea, vomiting, a whole host of side effects that go along with it.
So, we have this need and we do not have an alternative, but at the same time, the drugs are causing so many problems of various kinds.
That is where the research really comes in.
You could come up with a new drug, that is not an opioid, that is efficacious for relieving pain and avoids this problem. You can come up with a new kind of opioid that does not have the side effects, to avoid addiction and constipation and all the rest of it.
That is where I am at in my research, but we need new ways to manage this problem and to help people by getting a better drug out there that could relieve pain without all the severe side effects.
Why are opioids so effective at treating chronic pain?
Opioids hit your system at multiple levels. You have this pain pathway that starts in your skin, goes up your spinal cord, and up into your brain. But pain is not just one thing, it is not just a sensory experience. It has emotional components and it has cognitive components.
So, how you think and feel about pain actually has a big impact on how you feel pain, and then there is the sensory aspect, as well. There are all these different levels that pain is processed and sensed in your body, and opioids are blocking that at every single level.
There are opioid receptors in the nerve terminals in your skin, spinal cord, and brain as well as in the emotional and cognitive pathways that regulate pain.
Therefore, when you take an opioid, it is hitting pain at all those different levels, all those different aspects. That is part of what makes them so effective.
But at the same time, they preserve normal feeling and normal function, which is really important.
You could take an anesthetic or a nerve blocker, and sure, you are not going to feel any pain, but you will not feel anything else either. Long term, that is not really much of a solution.
Opioids are so effective in hitting pain in all those levels, but it does not affect normal functional feeling and proprioception, and all those other senses that a nerve blocker, for instance, will knock out.
Of course, what also makes them not effective is that the opioid system is not only present in that pain pathway. Evolution is a scavenger, so it uses these tools in multiple places.
Therefore, you have opioid receptors in your gut that drive constipation, you have opioid receptors in the pleasure and reward centers in your brain that drive reward and addiction.
These are all separate from the pain pathway, but when you take an opioid drug, it is going to hit everything. You do not get to choose.
Why has the extreme side effects of opioids created a national health care crisis? What makes opioids so addictive in nature?
They are not the most addictive drug. If you are looking at dopamine release, which is one of the bases of addiction, in the reward center of your brain, morphine and opioids are a moderate releaser of these chemicals and a stimulator of these pathways.
The gold standard heavy one would be something like cocaine, which is much stronger. The thing is that you are not prescribing millions of people cocaine to manage their chronic pain. That is where the two problems intersect.
You have all these people taking sometimes high levels of opioids to manage their pain due to tolerance. Those doses tend to increase with time because you become tolerant to the drug.
You have to take more to keep the same level of pain relief, but that can make the addictive properties worse. Then there are some cultural and social factors in the United States that have made it worse.
This is really not my area of expertise, but we really prescribe way more opioids than other countries do, especially in the EU and the UK. So, just per person, we are prescribing more.
I think that is also a significant part of the problem, as well. If you can find other ways to manage your pain, if the cultural expectations around pain management are different and you are taking less of the opioid, or fewer people are taking opioids, you are not going to have the same severity of a problem.
Opioids really are a critical and important tool, but they have to be used appropriately. Most people that take them for managing their pain are not going to become addicted. So, we are talking about a small percentage, but a large number of people.
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Can you describe the role of the heat shock protein 90 (Hsp90) in receptor activation and pain relief?
That is something we are still figuring out. HSP90 has been studied for a long time, in the cancer field, mostly, so it has a really important role in the cell.
It has a lot of other proteins that it interacts with and it regulates, and it controls a lot of cell processes.
A long time ago, people figured out they could use this for cancer. If you give someone a HSP90 inhibitor, it kills cancer cells and leaves normal cells alone.
Therefore, there was a lot of studies in the cancer field, but there really has not been a lot of studies on this important protein outside of the cancer and cell biology fields.
We ran across this protein when we were digging through databases. I had just started my lab and we were trying to find new targets to look at that could be regulating opioid receptor function, and we ran across this in a proteomic study.
We tried it out in the lab and saw these big effects. Now, the interesting thing is that what we are finding is that the role of HSP90 is quite specific, depending upon which part of the central nervous system you are talking about.
When we give an HSP90 inhibitor to the brain, it blocks opioid pain relief. So, you give this inhibitor, the mice experienced pain, even after being given the opioid. Of course, that is scientifically interesting, but that is not really what you want from a therapeutic point of view.
Our breakthrough came with this recent study where we did the same experiment but carried it out on the spinal cord instead of the brain and we saw the opposite effect.
If you give an HSP90 inhibitor in the spinal cord, the pain relief is greater, and it is without increasing the side effects and producing sedative or other off-target properties. The pain relief is just better.
We have identified some of the molecular mechanisms, but this is something you could potentially use translationally because if you have these inhibitors in a person, their pain relief is better, but the side effects are the same or improved so you can give less opioid drug.
If you give half the dose, the pain relief stays the same, but the side effects are going to be half or at least reduced and reducing your chances of addiction and other side effects.
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How could Hsp90 inhibitors be used to make pain relief more effective without increasing side effects?
We are finding more subtleties of the system as we go along.
In the study that is currently published, as well as our earlier studies, we used what is called a [non-selective] HSP90 inhibitor, so it hits all isoforms.
There are four different isoforms of HSP90, and it hits all of them equally. When we give this non-selective inhibitor in the brain, we see the reduction. Then we give it in the spinal cord, we see the enhancement.
When we give this non-selective inhibitor though, systemically, how a person would want to take it, by mouth, for instance, rather than being injected into your brain, we found that the system looks like the brain. The pain relief was reduced. That is part of the paper that has been published now.
So, that is not helpful. If the only way you could take these drugs was to inject them into your spinal cord, that is going to be a small number of patients that are going to be better.
We have really found a way around this and we have found that different isoforms of HSP90 are active in the brain versus what is active in the spinal cord.
When you give an inhibitor that is selective to the isoform that is only active in the spinal cord, you can take it by mouth, you can inject it into the bloodstream and the response is going to look like the spinal cord, the pain relief is improved.
The future of this work is an isoform-selective HSP90 inhibitor that we are currently developing right now that you could take by mouth and would have this great benefit. That would be translationally beneficial and would help the greatest number of people.
If the side effects of opioids can be decreased, what does this mean for public health?
I always try to think of the humanistic component. First, an improvement in quality of life. That is more people that are having a better life, that do not become addicted, that also do not have the other side effects.
These other quality life aspects are all improved such as improved management health too.
But you also have other benefits too. You have economic benefits, people that have less time off work and you have social benefits too.
If you do not have as many people becoming addicted, you do not have all the bad affiliated effects with it. Everything from the need for policing to the degradation of individual lives, emergency room visits, the deaths.
Potentially all of those things could be improved by ways to make opioids more effective.
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Do you believe that the number of people suffering from opioid addiction could be decreased if Hsp90 inhibitor drugs are manufactured?
We have the data to show this would be true, and I think we can decrease it.
It is not going to go from 40,000 to zero, because this does not really do anything for a recreational user that becomes addicted.
This is just going to be chronic pain patients who have become addicted. There is a lot of disagreement in the field as to how many chronic pain patients become addicted, but there is a pretty good number of them.
So, I do think it is going to have an impact on them, but it is not going to be a massive total thing. It is going to be a moderate but significant impact on people that become addicted.
What further research needs to be carried out before this research can be used in clinics?
One of the most important things to remember about this work is that we are obviously very excited about it, and I believe in it a lot, but this has all been done in mice.
So, we need to show that this translates. Right now, we are developing those isoform-selective inhibitors and those are all in the preclinical stage, where we are testing them in cells, and we are testing them in animals.
Once we get those, maybe four or five years down the road, if we can get those to the point where we show a good safety profile on these, we can get the FDA approval to start testing these in people.
That is really when we are going to be able to make the determination that this is really beneficial in humans. Then in the meantime, hopefully, we can get some donor tissue samples and some human tissue to try to look at the molecular aspects, but you cannot tell pain relief from cells in a dish.
Ultimately, these need to be tested in people, and that is going to require a little bit of work to get to that point.
What are the next steps in your research into opioids?
We have a lot of different directions we can go.
One of the most important things will be the translational aspect. I have a big grant that is currently being reviewed to help develop the isoform-selective inhibitors, which we really think are going to be potentially beneficial in people.
That is one avenue that we are pursuing, but there is also a lot of real basic science work that needs to be done. We have really only scratched the surface at this point.
Why is it different between the brain and the spinal cord? What are the specific molecules involved? We have identified some, but we have identified three or four, not the 50 or 60 that are probably involved.
Also, what are the molecular mechanisms? Which types of cells and neurons are these expressed in and exactly how are they affecting neuronal function? So, there is a lot of basic science work to be done to really understand how the system works too, as well as the translational human-centered research.
Finally, I want to acknowledge, first of all, my graduate student, Dr. David Duron. He defended his PhD based, a large part, on this work.
He did 90% of the work and really did a tremendous amount of work. Other collaborators include Dr. Wei Lei at Presbyterian College and Dr. Brian Blagg at the University of Notre Dame, who is an expert in HSP90 medicinal chemistry. He is making the HSP90 isoform-selective inhibitors.
Also Dr. Paul Langlais at the University of Arizona, my colleague, he did the proteomics work, where you look at a very broad level, all the different proteins that are being changed in the spinal cord when we give these inhibitors and helped us identify some of the new molecular players that are involved in this work.
Therefore, all of those collaborators were key members of the team and without any of them, this would not have been successful.
Where can readers find more information?
My faculty profile: https://profiles.arizona.edu/person/jstreicher
My bibliography: https://www.ncbi.nlm.nih.gov/myncbi/john.streicher.1/bibliography/public/
This paper: https://stke.sciencemag.org/content/13/630/eaaz1854
About Dr. John Streicher
My research program is focused on identifying the signaling regulators that link opioid receptor activation by drugs like morphine to behavioral effects like pain relief and addiction.
By understanding this complex signaling process, we can intervene to selectively improve the benefits of opioid drugs like pain relief while relieving the terrible side effect burden, especially addiction.
I am currently an Assistant Professor in the Department of Pharmacology in the College of Medicine at the University of Arizona.
I earned my Ph.D. under the mentorship of Dr. Yibin Wang at UCLA, followed by a postdoctoral fellowship under the guidance of Dr. Laura Bohn at The Scripps Research Institute – Florida.
I was faculty in the College of Osteopathic Medicine at the University of New England from 2012-2015, before joining the University of Arizona in my current position in 2015.