Dr. Elliot Hersh Q&A

DR. ELLIOT HERSH

Professor, Dept. of Oral & Maxillofacial Surgery/Pharmacology

How did you get involved in research? What got you interested in it? Actually, when I was a dental student, research wasn’t even a twinkle in my eye. During my junior year, a new faculty member came in at Rutgers University. His name was Stephen Cooper and he had gotten his dental degree from University of Pennsylvania and his PhD degree from Georgetown University Medical School. He taught a course in the beginning of my senior year, called “Clinical Therapeutics,” which put a clinical flavor on the basic pharmacology course that we had. After that I was hooked. He was by far the best teacher I had in all of my dental school training. That January, two postdoctoral fellowships became available for graduating dental students; one was in Immunology with a different faculty member and one was in pharmacology to spend the year working with him. So, I applied, and the rest is history. Within the first 3-4 months of that one-year experience, another faculty member D.M.D. PhD came on named Paul Desjardins, who is a respected dentist/pharmacologist. They decided they wanted to send someone over to the medical school to get a master’s degree. They’ve never done that before. I decided that in order to really get a better understanding of science, ask hypothesis driven questions, be able to write up scientific data, and get things published in journals, this training would be great; and that led to a master’s degree. It also led to the first paper I ever published in “Anesthesia Progress” called “The Effect of Intravenous Meperidine on Various Reparatory Parameters in Normal Volunteers.” Meperidine is a very old opioid. It was a main stay of sedation regimens. We wanted to look if we could pick up some of the pre-morbid signs of respiratory depression at therapeutic dosages, and that was my first bonified research project. Toward the end of that master’s degree, I realized that if I wanted to learn science to a greater degree, I would need to get a PhD. So I ended up flipping over to the medical school at Rutgers, and they took me, they never had a dentist before. I ended up doing my PhD work with a professor, George Condouris. He was one of the first people to describe that local anesthetic action is due to a blockade sodium influx, so this was a perfect match.

Both my MS and PhD thesis advisors allowed me to practice dentistry part time so that my wife and I didn’t starve to death. At the time, I applied for an NIH postdoctoral fellowship and it took me two shots to get it, as it usually does. The second time around I was funded and that suddenly put me at a salary level almost equivalent to an assistant professor. So I think having that funding played a role in me being appointed to an assistant professor here. It was a great learning experience as far as getting your writing critiqued, not taking things personally, and getting your research off the ground.

What were some of your previous research projects? My biggest claim to fame was this study at Penn with 210 subjects in 11.5 months-all wisdom teeth extractions. I did the study that supports the marketing claims that: “for tough pain nothing works better than Advil liquid gels, not even extra strength Tylenol.” It wasn’t even my conclusion at the end of the paper, that wasn’t the main focus of the study. But, it was clear that this rapid release formulation of solubilized potassium ibuprofen had much greater peak affects even at 200 mg, and much more staying power than maximum doses of acetaminophen (1000 mg). We did another pivotal study here at Penn that helped get a rapid release formulation of diclofenac FDA approved. Post-surgical dental pain is driven by inflammation and these NSAIDs work as well if not better than addictive opioids. I have been studying non-addictive pain relievers for the greater part of 30 years. The neat thing that we’ve been doing now is trying to predict who the best responders to non-addicting NSAIDs will be prior to surgery, because the time-action curves that I put in papers and give in class are averages. And even in cases with a super-duper pain reliever that works great on average, 15-20% of individuals said it was ok but they needed something more, and 5% said it didn’t work at all. My other field of research is on local anesthesia. We have done pivotal studies here with injectable and topical anesthetics that put a lot of drugs on the market. We had a large study involving topical benzocaine, an over-thecounter gel. The FDA challenged us to see if it works on toothache pain. We found that the maximum strength lasted about 20 minutes

longer than the normal strength. I have to give a lot of credit to my research coordinator, Stacey Secreto. I may be a lot of the brains behind the operation, but she’s the one that gets all the data. That was a study that really needed a lot of good timing. We noticed that most of our patients came in on Mondays and Fridays. They were triaged in the oral medicine emergency clinic and were sent to the oral surgery or endodontics clinic for definitive treatment in the following hours. So, we had roughly a 2-3 hour window to approach them and suggest this study. We didn’t advertise that there was $50 compensation because then everyone would claim to have toothache pain. You always should give people compensation for their time, but you can’t coerce them. Another part of this study was analyzing how well people self-administered the correct dosage of the medication. We found out that about 80-85% of them actually followed the label and applied the recommended dose. Only 15-20% were using it in excess. The problem with excess benzocaine administration is methemoglobinemia. There was no evidence of it here.

What is some of the research that you are currently working on? The most exciting stuff that I am doing right now is a collaborative project between myself, my research coordinator, some of the oral surgery faculty, and individuals from the Institute of Translational Medicine and Therapeutics. I became involved with this group simply by going to their meetings. They have a specialized group that focuses on NSAIDs called Personalized NSAID Therapeutics Consortium (PENTAGON). An MD/ PhD Neurologist, John Farrar, and I presented to this group what we planned on doing. We received funds from Pfizer to do our second functional brain imaging study, to determine what pathways of the brain light up when patients have post-surgical dental pain and what changes when they go from pain, to pain relief. We wanted to go to fMRI instead of SPECT so we could put people in the scanner and continuously monitor cerebral blood flow as the pain ramped up or down. We would actually wheel them from the oral surgery clinic at Perelman to the basement of HUP to the fMRI. We performed a double blind study, giving them either rapid release ibuprofen, in this case the sodium film tab preparation of Advil, or placebo. But right before we started we presented at the PENTAGON group, and Katherine Theken PharmD, PhD and Tilo Grosser, an MD cardiologist, asked if we could add some blood and urine samples to the data. So we put that amendment in. It turned out that while the brain imaging data was really interesting and the classic pain areas lit up with orange and red areas in the thalamus and anterior cingulate gyrus, once participants received the medication all of these areas turned blue and returned to normal; with the placebo group, the areas stayed red. That was pretty neat, but even neater was the precious blood samples and urine that we collected. With this type of research, you can’t be an expert on everything. You need to work with others who have different areas of expertise to get any sort of funding and answer hypothesis-driven questions. Through these samples, we were able to identify two phenotypes of ibuprofen responders. On average, ibuprofen overpowered the placebo with statistical significance. But if you look individually at patients, there were 10 patients with an average pain score of 7 out of 10, and when dosed with rapid release ibuprofen, at 4 hours post-dosing they didn’t need anything else. The other group of nine needed another pain reliever between 90 minutes and 3.25 hours. Everyone in the placebo group needed something in 1.25 hours. We also found that those who were the full responders made the most prostaglandins after surgery. So with partial responders, yes they have pain, but they may have some other mediators that are also driving their pain. Now we’re doing a bigger study with 80 people. We’re looking at oral microbiome, pro-inflammatory cytokines, sex differences, and genomics. We received a grant from the Center of Precision Medicine to see if there is a way to personalize analgesic therapy.

What are some of the most difficult parts of research and what keeps you going? Some of the most frustrating parts of research is slow enrollment. We’re dealing with human research subjects and a lot of personalities with co-investigators. You have to accept that people have different personalities and different mindsets. Collaborating with others from different schools here at Penn is absolutely fantastic. I have learned so much about brain scans. I don’t have to be an expert on it. It was very frustrating at first, because all of us at Penn put our armor on. But you have to have the guts to ask “wait, I don’t understand, what does this mean? What does noncoding RNA do?” What keeps me in the game? There are three reasons: 1) I can translate my research into the classroom. I have been very passionate about the addicting effects of opioids ever since 1990, way prior to the zenith of the crisis. 2) The ability to publish things for clinicians about opioid alternatives is gratifying and I think it’s reducing opioid prescriptions. This pain genomic stuff is really slick stuff and even though I’m an old dog, I like to learn new tricks. 3) From a teaching end, I enjoy being around students. The most important thing I do is translating my research to DMD students, residents, and people in private practice.

Do you have any advice to students who are interested in going into research after dental school? The DMD degree gives students a lot of opportunities. The first project that I think you should choose when approaching a mentor is something that you have a reasonable chance of publishing. One of the issues with some of my studies is that they’re long term and performed while you’re in class. I do have students sometimes, but it is a major commitment. You need a mentor who enjoys working with students. Dental school is not easy. I remember my plate was pretty full back then and I don’t know if I could have handled going into someone’s lab in addition to everything else. Do some work on your own — don’t be afraid to ask questions. Ask your mentor some questions if you don’t understand things well after reading the papers. Schedule your time well when you’re going to be in the lab, when you’re going to be studying, and when you’re going to be having some enjoyment. Having no fun can sometimes lead to becoming a miserable person. That’s my major advice. Be prepared for experiments not working out. That’s why they call it research. Be prepared for research to occasionally not go in the way that you thought it would go.