Tapering Opioid Dosage; Citing Retracted Studies: It’s TTHealthWatch!

TTHealthWatch is a weekly podcast from Texas Tech. In it, Elizabeth Tracey, director of electronic media for Johns Hopkins Medicine, 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 what happens when a study is retracted, is spinal fusion necessary, tapering opioids, and FDA approval of medical devices.

Program notes:

0:40 Treatment of slipped discs

1:40 Hadn’t responded to conservative therapy

2:40 Increase stiffness

3:25 Tapering opioid dosage

4:25 More overdose in those tapered

5:25 Willing to taper slowly

6:00 FDA approval of medical devices from 1976-2020

7:00 Class 3, lifesaving or life-harming potential

8:00 Can only deal with information you have

9:05 Approval in Europe faster

9:22 Retraction of studies and subsequent citation

10:25 Maintain attention scores

11:25 Cited in new articles

12:46 End

Transcript:

Elizabeth Tracey: How should we manage people who have been on opioids for a long time?

Rick Lange, MD: FDA regulation and approval of medical devices over the last 44 years.

Elizabeth: What happens in the scientific literature when a citation is retracted?

Rick: And if you have a slipped disc, do you need to have your spine fused?

Elizabeth: That’s what we’re talking about this week on TT HealthWatch, 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 the dean of the Paul L. Foster School of Medicine.

Elizabeth: Okay, Rick. Why don’t we start first with the New England Journal of Medicine, because this is a long-standing issue about how to manage folks who have lumbar spine issues.

Rick: This is a condition called degenerative spondylolisthesis. Whoa! What that means is a slipped disc. Usually when people have slipped disc, they have a disc that’s bulging, leg pain, back pain, restricted activity, and we usually treat that conservatively and most people respond. But some don’t, and if they have symptoms that persist over a long period of time despite non-surgical therapy, then they are recommended for surgery oftentimes.

The old surgery used to be what’s called a decompression surgery or laminectomy. That’s to take the pressure off the nerve root to relieve the pain. But more recently, 90% of the procedures in the United States have also been associated with spinal fusion at the same time. That’s the use of screws and rods, bone grafts, to actually fuse the vertebral bones to prevent additional slippage of the disc. Is that really necessary?

So this was an open-label, multicenter, non-inferiority trial that involved patients that had symptomatic bulging disc and they hadn’t responded to conservative management. It was just a single disc that was slipped. They had not had previous surgery. It wasn’t a severe narrowing and they were randomized to either have just decompression or decompression with spinal fusion.

Two years later, what are their symptoms, how disabled are they, and how often do they need to have a reoperation? Does spinal fusion actually help? What they had discovered in a group of over 267 patients — and these are people by the way that had symptoms for, gosh, more than a year — spinal fusion added no benefit to just doing decompression laminectomy with regard to symptoms or disability. Now, there was a slightly lower risk of reoperation, about 9% in the fusion group versus 12.5% in the decompression-alone group.

Elizabeth: Of course, this is a positive outcome as far as I’m concerned because it’s significantly less intrusive with regard to the surgery itself. Also, what we know about those devices that are inserted in the spine is that they increase stiffness. If somebody is involved, for example, in an accident afterwards, this can be a bad place to have a fracture.

Rick: Right. Oftentimes what happens when you do the spinal fusion is it fuses those two vertebral bones and it reduces flexibility there, so it increases stress on the other ones. So oftentimes people need operations in the adjacent vertebral bones.

Elizabeth: So many people have this particular problem. In fact, cadaveric studies have shown us that in fact the majority of us are going to have degeneration in that area of our spine as we age.

Rick: Right. About a decade ago, we spent over $13 billion, a higher cost of this than other surgical procedures such as knee and hip replacements, even percutaneous coronary intervention — that is, putting stents in patients.

Elizabeth: Let’s turn now to JAMA. This is another issue that I think is really important and timely. This is the association of tapering opioid dosage in people who have been on long-term opioids and whether that’s associated with mental health crises and other problems.

The looked from 2000 to 2019. They looked at this issue of shall we taper down somebody’s opioids when they have been on them for a long time? That they defined as at least a 15% relative reduction in their mean daily dose during any of six overlapping 60-day windows, within a 7-month follow-up period.

They in their final cohort had 113,000 + people. Among those patients who underwent dose tapering, about half and half women and men. Their mean age was 58. In fact, those post-tapering periods were associated with an adjusted incidence rate of 9.3 overdose events per 100 person years for those who were tapered, versus 5.5 in those non-tapered periods.

They also had more mental health crises per 100 person years, the folks who were tapered than those who were not. The editorialist takes a look at this and says, “Wow, we need to rethink what we’re doing here. Everybody thought this was a good idea.”

Rick: Elizabeth, I was surprised at this. This is kind of a paradoxical increase in opioid-related harms associated with decreasing opioid use. I mean, you think, “OK, someone is on a high dose of opioids. The first thing we need to do is let’s get them off of that to decrease their risk of overdose.” And what happens, as you said, is if you withdraw them, especially too quickly, you do just the opposite. You make things worse. I was really surprised at this.

Here is the conundrum for physicians. We’re told to taper patients. We know that a high dose is associated with an increased risk of overdose. We’re afraid of tapering too slowly because we don’t want to continue prescribing opioids to someone when we know that they shouldn’t be on them. But what this study instructs me is that we need to develop a relationship with the patient, we need to find out what their needs are, we need to be willing to taper over a slow period of time, even if that requires prescribing opioids initially, and then work with the patient together so we can do it in a safe manner.

Elizabeth: Exactly. The other thing that the editorialist notes is that patients who are prescribed opioids for chronic pain and those with opiate use disorder report that they feel substantial stigma coming from clinicians. So establishing that therapeutic relationship and that trust is going to be really critically important to getting somebody tapered.

Rick: You’re right. This is a shared decision process.

Elizabeth: Indeed. So where are we now?

Rick: Another article in JAMA and this is really pertinent. We usually record early in the morning. We’re recording late at night because I was chairing an FDA panel. This particular study looks at FDA regulation and approval of medical devices from 1976 to 2020. For individuals that have always wondered, like, “How does the FDA work and how do they regulate stuff?,” what you’re going to discover is since the FDA really began regulating things in earnest in 1976, they have a number of different pathways available. It’s meant to help speed things along. They have done that, by the way, needing to assess fees on the manufacturers to provide them the resources to accomplish this.

In 2017 and in 2018, there were more than 18,000 manufacturers producing an estimated 190,000 distinct medical [devices]. How does the FDA regulate that? Well, they divide them into classes based upon how safe they are. Things like a band-aid or a thermometer, they’re called Class I and there is really very little regulation.

On the flip side, there are what are called Class III that could potentially be life-saving or life-harming devices. If they are new, they go through a process called a pre-marketing approval. They usually indicate they have a study that proves that they’re both safe and effective. When that’s done, by the way, they can be approved. And the FDA, in general, about 1% of their products they evaluate goes through that pre-marketing approval. They usually do about 30 per year.

Most of them come through what’s called a 510(k). That’s a regulation that says, “Listen, if you’re making a device and it’s like another device and we’ve already approved it, it’s equivalent, then you just show the data to the FDA, it doesn’t have to go to a panel like I chaired today and we’ll approve it.” And 99% of devices are approved in this particular way.

Elizabeth: Right. There are, however, noteworthy cases where things that have been put forward as very similar to things that have already been approved really aren’t all that similar, and there are substantial changes and in some cases have resulted in harm. And so this is a situation that I think we need to scrutinize a little bit more carefully, just like accelerated approval for drugs.

Rick: How does the FDA deal with that? Well, you can only deal with the information you have in front of you, and sometimes that’s limited. A study may be done on a couple of hundred or a couple thousand patients and you may not be aware of complications associated with the device until it has been in hundreds of thousands of patients followed for not months but years.

Let me give you a couple of examples. There was a particular hip device that was used in hip replacements that started to break down. We know that using a mesh for gynecologic surgery has complications. Now we didn’t realize that until it had been implanted in over 750,000 women. We followed them over the course of years. Now when that happens, the FDA can ask for a post-marketing study or look at the data and retract the device based upon the information that’s available. That is the FDA trying to preserve our safety, but at the same time not slow down the process that gives us devices that we need. It’s always a very fine balance.

Elizabeth: Spoken like someone who has just chaired a committee. I am a lot more harsh with regard to these procedures because I have spent so much time reporting on the harms of some of these things that come across the transom as approved.

Rick: Right. Clearly, if you go to Europe, things are approved in Europe faster than they are here because there is less scrutiny associated with it. They are not perfect, but I can tell you I have worked with them now for over 12 years and they really struggle very much to try to get it right.

Elizabeth: Okay. We’re going to agree to have slightly different viewpoints on this particular one. Now we’re going to turn to JAMA Internal Medicine. Speaking of striving to get it right, wow, we have a problem with the medical and scientific literature.

This was a problem that I think most noteworthily many of us became aware of when a purported link between thimerosal and autism in routine immunizations was published in the literature and subsequently retracted. But, boy, look at how much damage that has done. And I would respectfully suggest that even some of our recalcitrant folks right now who don’t want to get COVID vaccines are probably thinking about the specter of that study in the back of their heads.

In this case, they took a look at two different studies, one was published online in The Lancet on May 22nd, 2020 and retracted on June 13th, 2020. They took a look at the Altmetric Attention Score and found out its score was 23,084. The second study claimed to investigate the association between cardiovascular disease, renin-angiotensin-aldosterone system inhibitor therapy, and COVID-19 outcomes. The first one was hydroxychloroquine. The second one was published in the New England Journal of Medicine, and, again, it was published on May 1st, 2020, retracted on June 4th, 2020, and still maintains this Attention Score of 3,727.

Then they looked at the number of citations that were still in place for the two retracted studies. Again, a startling amount of citations in other papers that were referring to these studies. This clearly is a problem. What are we going to do when studies are retracted so that people don’t keep on citing them?

Rick: Large studies, what happened was the data couldn’t be corroborated. As a result, these really good journals — The Lancet and New England Journal of Medicine — retracted the articles.

And you’re right. They were retracting articles and they are still citing them in the medical… when I say citing them, someone else is writing an article about hydroxychloroquine, they review it and think, “Oh, it must work. I am going to cite this other article that proves it.” Well, these were withdrawn.

As you know, besides serving on the FDA, I serve as an associate editor for a couple of journals. That falls on the reviewers and the editors to catch that. That falls on the journal to screen those things out so it doesn’t inadvertently come in the literature and keep giving these false notions or these false outcomes, or these false results.

Elizabeth: It’s great to put the onus on the editors. I am just wondering if we can’t somehow develop — we’ve got lots of international databases — some kind of international database that would just flag these things as retracted. When somebody attempts to put it into their reference page, it would say, “No, no, no.”

Rick: Elizabeth, that’s a really good thought. You’d think you need a database because some of these are in obscure journals, but these were, again, The Lancet and New England Journal of Medicine. These were like high-visibility journals.

But I think your point is well taken. We ought to be able to automate it so that when someone cites that you say, “No, no, no, no, no, no. That is not a study you should cite because it was retracted.”

Elizabeth: Well, we’ll see if that ever comes to pass. On that note, 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.