Sep 25, 2023

Fentanyl Death Trends; Food Additives and Heart Disease

by Rick Lange, MD, Texas Tech; Elizabeth Tracey, Johns Hopkins Medicine September 23, 2023

TTHealthWatch is a weekly podcast from Texas Tech. In it, Elizabeth Tracey, director of electronic media for Johns Hopkins Medicine in Baltimore, and Rick Lange, MD, president of the Texas Tech University Health Sciences Center in El Paso, look at the top medical stories of the week.

This week's topics include food additives and CVD, uncomplicated heartburn and cancer, MDMA and PTSD, and trends in fentanyl deaths.

Program notes:

0:40 Fentanyl drug overdose death trends

1:44 Shifted to stimulants along with fentanyl

2:40 Treat respiratory depression first

3:05 MDMA and PTSD

4:07 Improved with MDMA

5:08 Does increase HR and BP

6:07 Comparison with other drugs

6:40 GERD, esophageal erosion and cancer

7:40 Non-erosive does not increase risk

8:40 Repeat endoscopy?

9:00 Food emulsifiers and CVD

10:00 Very modest increased risk

11:10 These emulsifiers impact gut microbiota

12:25 End


Elizabeth: Are common food additives increasing your risk for heart disease?

Rick: Does uncomplicated heartburn increase your risk of cancer?

Elizabeth: Can MDMA help people with post-traumatic stress disorder?

Rick: And changing trends in fentanyl overdose deaths.

Elizabeth: That's what we're talking about this week on TTHealthWatch, your weekly look at the medical headlines from Texas Tech University Health Sciences Center in El Paso. I'm Elizabeth Tracey, a Baltimore-based medical journalist.

Rick: And I'm Rick Lange, president of Texas Tech University Health Sciences Center in El Paso, where I'm also dean of the Paul L. Foster School of Medicine.

Elizabeth: Rick, how about if we start with addiction. This is a report on a very concerning new combination of drugs that's accounting for a large number of overdose deaths.

Rick: It's titled "The Transition to the Fourth Wave of the Drug Overdose Crisis," so let me take a step back, Elizabeth. The United States overdose crisis has really escalated substantially over the last four decades, but there has been a shifting profile of the drugs that have been responsible for this. The first wave of the overdose crisis began in the late 1990s to early 2000 with deaths associated with prescription opioids. The second wave began in about 2010 and it was a shift to heroin overdoses. The third wave began in 2013, primarily driven by illicit fentanyl analogues. Unfortunately, now we're reporting the fourth wave of the U.S. overdose crisis and it involves polysubstance, fentanyl-overdose deaths.

They report unfortunately the percentage of U.S. overdose deaths involving both fentanyl and stimulants increased from 0.6% a decade ago to now almost a third of all fentanyl overdose. Early on, fentanyl was most commonly associated with prescription opioids or benzodiazepines or alcohol, but that has now shifted substantially across the United States so now stimulants are the most common drug class found in fentanyl-involved overdoses in every state in the United States.

Elizabeth: Yikes, and of course we know this is against the background of CDC data reporting that yes, indeed, these deaths continue to accrue at an increasing rate. When we look at those year-to-date kind of estimates -- which of course, they're underestimates of these deaths -- there are over 110,000. I have a question about reversal because, of course, fentanyl is tough to reverse even with naloxone. What happens if you've got stimulants on board?

Rick: Elizabeth, that obviously complicates the issue not only to the user, in which case it increases the risk of death, but also to the physician. This presents novel health risks and also public health challenges, because one has to deal with not only with the naloxone, but also with the stimulants.

Elizabeth: So what do you do?

Rick: Well, Elizabeth, it would depend primarily on what the presenting symptoms are. If they are respiratory depression, you treat that initially with naloxone. The stimulants, however, can have other side effects. They can increase the risk of stroke or heart attacks, or increase the blood pressure or heart rate. Those may need to be dealt with at the same time. Very complicated. Unfortunately, you highlighted the fact that it increases substantially and disproportionately affects racial/ethnic minority communities as well. Again, a public health crisis that needs attention.

Elizabeth: Since we're talking about drugs, let's turn to Nature Medicine because this is a report utilizing the frequently illicitly used drug MDMA as a treatment for moderate-to-severe post-traumatic stress disorder. Which is interesting, isn't it? We have many examples of that including psilocybin recently.

This is actually a phase III trial. It enrolled folks with, as I said, moderate-to-severe PTSD and administered half of them about with this MDMA therapy. The other half got placebo. This was also concomitant therapy with a trained therapist who was going to be present for this. About 27% of their people had moderate PTSD and 73% had severe PTSD. It also turns out that they had this condition for about 16 years, which seems really excruciating to me to be dealing with PTSD for that long.

They found that utilizing different assessments they were able to reduce the symptoms and improve this PTSD for the folks who actually got the MDMA much more than they were with the people who had the placebo. They also found that there were seven participants who had severe treatment-emergent adverse events. There were no deaths or persistent adverse events and so they say, "We advocate for using MDMA in this population."

Rick: Several caveats. First of all, it's a fairly small study. There were 53 patients that received MDMA and about 51 that received placebo. Second was, it was a fairly short duration of follow-up. You have to look at what patients were not enrolled in the study -- patients with a high suicide risk, those that had other personality disorders, or those that had underlying cardiovascular disease -- because the thought is in these particular individuals the MDMA may either increase the risk of suicidality or increase the risk associated with the comorbid conditions, or even cardiovascular disease, because MDMA does increase the heart rate and blood pressure; it did in a not-insignificant number of these individuals as well -- usually transient.

I consider this a preliminary study and I think it warrants larger studies to see whether these results are sustained over a long term and whether it really is safe and effective.

Elizabeth: I agree and I think that one daunting statistic in here is that they say that 5% of the U.S. population is experiencing PTSD on a yearly basis. That's a lot of people. One of the most dangerous types of this is what's called dissociative. It fortunately does not occur in all that many of the people overall who have PTSD.

The other thing I found extremely objectionable about this paper is that they didn't really describe exactly what they did. You had to look at the diagram to see how this whole thing worked out. It turned out that they needed multiple sessions of this drug and also needed multiple sessions with the therapist in order to have this impact. I would look for a comparison between this and psilocybin, which is a single-use kind of a drug, to achieve some of the same results.

Rick: Or the other ones that are FDA-approved are the selective serotonin reuptake inhibitors, like sertraline and paroxetine, and about 55% or 60% of people respond to those. You're right. In the future, we need to have comparison studies with other therapies that we know are effective.

Elizabeth: I would finally just note for everybody out there who is a clinician that this MDMA falls into a category that's now being called entactogen that might be helpful.

Rick: Let's move on to something that's a fairly common thing and that is what I call heartburn, by medical terms GERD. It occurs in about 20% of adults in high-income countries. We know that when people have reflux they have symptoms and oftentimes when one does an endoscopy, that is, to look down into the esophagus, one can see erosion or ulcers. We know that that increases the risk of cancer of the esophagus about three-fold. But what about those individuals in whom endoscopy is done and you actually don't see erosion? Does that predispose to cancer as well and therefore it would warrant aggressive therapy?

The investigators looked at almost half a million of adults who underwent endoscopy. About a half of them had erosive gastroesophageal reflux disease and about the other half did not. They just had plain old reflux.

They followed these individuals for up to 31 years. What they discovered was compared to the general population, those that had erosive esophagitis, again, it increased the risk of having esophageal cancer threefold. But if you didn't have erosive reflux, it did not increase your risk. These individuals had a single endoscopy. Their risk of having esophageal cancer was no different than the general population.

Elizabeth: Let's talk about relief of symptomatology secondary to gastroesophageal reflux. Are these folks all still on PPIs or other interventions?

Rick: Individuals that don't, you can just treat them symptomatically and that usually is a short course. There are some complications associated with the long-term use of chronic PPI, so treating symptomatically is fine.

Elizabeth: I'm really interested in some of the other factors that are associated with this and also some of the conservative strategies relative to management. I'm thinking about avoiding consumption of a lot of food before bed, elevating your head, and what about the relationship with obesity.

Rick: In fact, all of those things predispose individuals to having GE reflux. In addition to pharmacologic therapy, most physicians I know will prescribe the behavioral or lifestyle changes that you mentioned. Those things all decrease the risk of GE reflux, so I'm glad you mentioned it.

Elizabeth: Finally, I guess I would say that the definitive test clearly is to scope somebody and see whether they have erosive disease.

Rick: Absolutely. Again, the nice thing this study shows is if you have endoscopy that shows that there is no erosion, it doesn't appear necessary to repeat that.

Elizabeth: Staying in the BMJ, then let's turn to something that I was interested in this because I feel that we're looking for the next dietary Darth Vader and recalling, of course, fat, salt, coffee, and so forth. This one is a big study taking a look at food additive emulsifiers. These are virtually ubiquitous in packaged foods. This is utilizing a French population that they have been following these folks for quite a while.

They have 95,000-plus adults in this NutriNet-Santé study conducted between 2009 and 2021. All of the people who were eligible for this study had completed at least three 24-hour dietary records during their first 2 years of follow-up. Their mean age, 43 years, and 79% were women. They looked at cardiovascular disease outcomes during that time and they also evaluated the consumption of lots of different food additive emulsifiers.

There was a very modest increase in cardiovascular disease risk for people who did consume these things. They cite that 30% to 60% of dietary energy intake in adults in Europe and North America is provided by ultra-processed foods that have a high level of these things. However, compared to so many other things that we're worrying about, I don't think I'm going to worry about this one.

Rick: You're talking about a 5% increased risk. They tried to adjust for a number of different risk factors -- things like age, sex, gender, smoking, obesity, BMI, and physical activity. They didn't even mention diabetes, which is a big risk for cardiovascular disease.

Ultra-processed foods are not nearly as healthy as fresh foods or the Mediterranean diet. Regardless of what it is in ultra-processed foods, the less of those that we ingest, the healthier we'll be overall. That would be the major message.

Elizabeth: I also wonder about if we eliminated these, what would we substitute? Because shelf-stable foods are an important part of almost everyone's diet.

Rick: Especially those individuals that don't have access to fresh fruits or vegetables.

Elizabeth: One aspect of this I didn't really think about is the fact that these emulsifiers, just as food does just in general, has a huge impact on our gut microbiota. I would like to see some assessment of inflammation in the gut and whether these things exacerbate or promote that.

Rick: No. But, Elizabeth, it does reference other studies that have shown in animal models and in humans two things. One is, it does increase gut inflammation and it does change the microbiota, although usually in supraphysiologic doses -- much higher doses than what you usually consume.

Elizabeth: Let me just also add that I thought it was fascinating that the highest intake of emulsifiers -- those folks who consume more of them -- were more likely to be younger, have a higher BMI, be never smokers, and have higher education and physical activity levels.

Rick: It does help us target this information. I mean, do you want to get this out to individuals that are more likely to eat ultra-processed foods? Those are the ones who need to receive this message.

Elizabeth: Okay. On that note, then that's a look at this week's medical headlines from Texas Tech. I'm Elizabeth Tracey.

Rick: And I'm Rick Lange. Y'all listen up and make healthy choices.