ANDREW KOLODNY, MD. This talk was presented at the 2015 PharmedOut conference on The Real Risks of Rx Drugs.

Transcription

1

2 2 ANDREW KOLODNY, MD This talk was presented at the 2015 PharmedOut conference on The Real Risks of Rx Drugs. This is the opium poppy. And as you see at the head of the middle of the flower, there's the poppy head, and it's from the poppy head that we get opium. The point I want to make just at the outset is I'm going to be talking about opioids. I'm using the term "opioid."

3 3 The term "opioid" refers to the natural occurring molecules in opium. And opium is really the sap from the poppy plant. So opioids include the naturally occurring molecules. And the other term for the naturally occurring opioids is opiate. But opioid also refers to the semi-synthetic opioids. And they are semi-synthetic because you start with opium to make them. So, for example, to make heroin, you start with morphine. To make hydrocodone, oxycodone, oxymorphone, hydromorphone, you actually start with the bain, which also exists in opium sap. And the take-home message here is that when we talk about opioid painkillers, when we talk about drugs like hydrocodone and oxycodone, we're talking about drugs that come from opium in the same way that heroin comes from opium. And in fact, the effects that hydrocodone and oxycodone produce in the brain are indiscernible from the effects produced by heroin. When we talk about opioid painkillers, we are essentially talking about heroin pills. Now, to say that hydrocodone and oxycodone are essentially heroin pills does not mean we shouldn't ever prescribe them. These are very important medicines for easing suffering at the end of life, and they play a very important role when used on a short-term basis, a few days, for example, after major surgery, after a serious accident. Unfortunately, the bulk of the U.S. consumption of opioids in the United States is not for end-of-life care or shortterm use, and I'll be talking more about that.

4 4 You'll hear our opioid problem described in different ways, and sometimes you'll hear the term "epidemic" used to talk about our opioid crisis. The CDC is using the term "epidemic." And in fact, the CDC was criticized for talking about our opioid overdose and addiction problem. They were criticized for using the term "epidemic" by industry supported organizations. And the CDC responded by saying, we don't use the term "epidemic" lightly. This is an epidemic. And, in fact, the CDC isn't just calling our opioid crisis an epidemic, they're calling it the worst drug epidemic in the United States' history. And the reason that they're using such strong language is on this slide. You see on the left here you've got this box that says "heroin." And over on the right you've got this box that says "cocaine." Those boxes are referring to drug epidemics. So, what you see here is the rate of drug overdose death in the United States during the height of the heroin epidemic in the 1970s. And then in the cocaine box you're looking at the rate of drug overdose deaths during the height of the crack cocaine epidemic in the late '80s, early '90s. Now, if you were to take this box and put it on top of this box and draw a line across, you would see that we have far more overdose deaths today than we had at the height of those two epidemics combined. Now, the CDC hasn't updated this slide in a few years, so I updated it by putting in the number of people who died of a drug overdose death in the United States in This slide came out in 2010 when the most current data was What we've seen each year since 2007 is that that bar has gone up, and up, and up, and up. So for the past 15 years, each year we've set a new record in the United States for drug overdose deaths. And then the very next year we break that record.

5 Now, the previous slide was showing you death from all drugs. This slide is showing you the type of drug people are dying from. And you know, I started off by saying that heroin is an opioid. Here on this slide, though, heroin is shown in green, the red is referring to prescription opioids. What you can see is that the sharp increase in overdose deaths in the United States has really been driven by painkiller overdoses. Now, since 2010, we've seen this green line go up very quickly. And so there's really been a spike. A 40% increase, coming down like this, since And there's this media narrative that's developed because of this spike in heroin overdose deaths that we're seeing more people dying from heroin as a consequence of a Federal crackdown on painkillers. That's not really accurate. 5 I keep asking myself, what crackdown are they referring to? There was just recent upscheduling of hydrocodone combination products, drugs like Vicodin were put into the Schedule II category where they belong. That didn't happen until It was in 2010 that we started to see heroin overdose deaths go up. It is absolutely true that people who are using heroin today, 4 out of 5 of them and probably 95% of the younger people have started with painkillers and switched. But this hasn't happened recently. From the beginning of the painkiller problem, people were switching from painkillers to heroin if they were young and having a hard time getting painkillers.

6 6 This graph, you're looking at whites on the left and African Americans on the right, and the color of the lines are referring to age groupings. I want you to look at the red line, which is referring to the age group 20 to 34 years old. What you're seeing there is that for whites, ages 20 to 34, heroin use has really just skyrocketed. For African Americans in that same age group of 20 to 34, we've seen a significant decline, and that downward trend has been in place since the 1980s. Similar for crack cocaine, as well. Young adults and adolescence in innercity communities are staying away from crack cocaine. "Crack is Whack" became the slogan. And there are still people in those communities with a crack cocaine problem or a heroin problem, but it's an aging cohort. Among whites we've seen a skyrocketing in heroin use. And again, these are individuals whose opioid addiction began with exposure to painkillers.

7 You'll hear the opioid problem described in different ways. You'll hear people talk about a prescription drug abuse problem, or heroin abuse problem. It bothers me when I hear people use the term "abuse" to describe the problem. I think it sort of makes people think that the problem we're dealing with is when you've got a bunch of people running around out there using dangerous drugs to feel good from them, and they're accidentally dying, and so the problem is people just behaving badly. And that's not really what's going on. The vast majority of overdose deaths are occurring in people who are addicted. There are certainly people dying of opioid overdoses who were not addicted and I have a friend who lost his daughter, Emily, to an OxyContin overdose. She was 17 years old. She was at a party the night before going to college. She took an 80-milligram OxyContin at the party. She was not an experienced opioid user; she had no tolerance. And that 80-milligram OxyContin killed her. She fell asleep at the party and never woke up. So that's an example of somebody who was not addicted who died of an opioid overdose. There are also the pain patient. The pain patient may be recently started on an opioid, or the pain patient who forgets that they took their 80-milligram OxyContin before going to bed, so they take a second one. And they don't wake up in the morning. And again, deaths like this are significant. But in studies of opioid overdose decedents, the vast majority appear to be people who had the disease of opioid addiction. And they got that disease more or less one of two ways. Either they were taking opioids recreationally and they wound up doing that a bit too much and got addicted, or they were taking opioids medically and developed addiction through medical use. So I'm going into great lengths to explain that our opioid crisis is really an epidemic of opioid addiction. And now I'm going to show you the epidemic occurring over time and in -- in color on these maps. So I'm going to show you a succession of maps now. 7

8 This is at the beginning of the epidemic. I would argue the epidemic began in So we're three years into the epidemic. And you can see that a few states are lighting up the states with the greatest number of people showing up to addiction treatment centers, state licensed addiction treatment centers, addicted to painkillers. The states with the highest rate show up as red or maroon. I want you to watch what happens to the color of this map as we go forward in time in two-year increments

9 And So what you can see is that in just about every state in the country we've seen a very sharp increase in the prevalence of people with the disease of opioid addiction. And when you have a sharp increase in a disease over a short period of time, that is the definition of an epidemic.

10 10 To make this graph, the same data that was used to make those maps, this is where that data came from. And you're looking at the demographics. And you glance at this. It's a little confusing at first. There's something actually very striking here. And I don't know if anyone's picked up on it yet. So you're looking again at the demographics of people showing up to addiction treatment centers saying that the primary drug they're addicted to is a painkiller. And some of this is not that unusual. So for example, the very big spike in early adulthood, that's what you see in addiction treatment settings. It's not that older people aren't getting addicted, but they're much less likely to wind up in addiction treatment programs. Younger people are more likely to have families that coerce them into treatment, or they are coerced by the courts. Something that's a little interesting is that you see on the left males and females. It's a similar height. If I showed you other drugs, for example, crack cocaine, you would see significantly more male than female. Heroin historically was much more male than female. Here they are similar. But what's really striking on this graph would be the racial break down. So the blue line you're looking at is referring to whites. Try to find other racial groups on the graph. So, for example, African Americans which show up as red. Barely see it register. Now this -- you

11 might be looking at this and thinking, well, maybe African Americans are less likely to wind up in addiction treatment. No, these are state licensed drug and alcohol treatment programs. In fact, you're more likely to see lower income individuals in those types of treatment settings. Again, if I showed you the crack cocaine slide, you'd see a red line for African Americans bigger than the blue line. This is real. To say that this epidemic is disproportionately white is an understatement. It is really striking how white this epidemic is. And it's even fair to say that it's protective to be non-white. And I think there's also a very important clue here as to what's been fueling the epidemic, because my explanation for this racial distinction has to do with the way in which doctors prescribe painkillers. And we know from studies that have been done that doctors prescribe opioids, they prescribe narcotics more cautiously when the patient is non-white. If the patient is black or Latino, the doctor is more worried possibly about the possibility of addiction, more worried maybe about diversion. When the patient is white, the doctor may feel there's very little to worry about. The pharmaceutical companies keep putting out paper saying we're under-treating pain in minorities. They're the ones actually sponsoring these studies that are showing this distinction. It's not that we're under prescribing opioids in minorities. We are over prescribing opioids to whites. Doctors should be prescribing cautiously, obviously, to all of their patients. So it's -- what you have here is it -- I would say racial stereotyping is having a protective effect. So, let's talk more about what's caused this epidemic. And I think the best answer to this question came from Dr. Lynn Polizzi of the CDC. Lynn was one of the original cofounders of PROP, Physicians for Responsible Opioid Prescribing. Lynn has had this issue of overdose deaths on his plate for quite a while was the first time he published any kind of data like this. And what he did in his study was in orange he plotted out overdose deaths from prescription painkillers. And then in yellow he plotted out sales for prescription painkillers. And what does that mean? That really means prescriptions. Patients don't walk into a pharmacy and say, oh, I'll have 120 Percocet. They walk in with a prescription. And what he was demonstrating is that, as the prescriptions for opioids began to soar, it led to a parallel increase in overdose deaths. What he was saying in his paper was that this epidemic has really been caused by the medical community. That as we began to prescribe opioids much more aggressively, beginning in the late 1990s, it led to this public health crisis. And this has become the CDC's chief speaking point about our opioid addiction epidemic. 11

12 12 This is their more current data, it's making the same point Lynn was making eight years ago. The green line on this graph is referring to opioid consumption, the red line is referring to opioid overdose deaths, and the blue line is referring to addiction. And the CDC's point is that as our consumption for opioids has increased, it's led to parallel increases in rates of addiction and overdose deaths. In 2008, here, the International Narcotics Control Board put out a report on global use of opioids. Their report indicated that the United States, with 5% of the world's population, was consuming 80% of the world's entire oxycodone supply. And they also pointed out that 5% of the world's population were consuming 99% of the world's hydrocodone supply. That was in And as you can see, the line has still gone up. The point the CDC is really trying to make with this slide is that until that green line begins to go down, we may not be able to bring this epidemic under control. Obviously you don't want the green line to go down to zero. These are essential medicines for end-of-life care and for acute pain. But obviously the green line needs to come down. Pharmacological companies, and the industry, I would use the term "the opioid lobby," because it goes beyond the pharmaceutical companies themselves. This includes the distributors, the wholesalers. It includes pill mill practices and even the chain pharmacies. The opioid lobby has really been saying that they don't like the CDC's message. They don't agree. They say that the green line should not go down. They say that a hundred million Americans have chronic pain, and that the green line can and should go up so that more patients have access to opioids. But, if we teach doctors what they call safe and effective opioid prescribing for chronic pain, if we teach doctors, they also call it the new paradigm risk mitigation strategies

13 for treating patients with opioids long term, if we teach them the right way to do it, we can have our cake and eat it too. We can make the red line and blue line go down. And unfortunately when you look at what they're really being taught in those programs, it doesn't work, and it really doesn't make sense. So I said the opioid addiction epidemic began in And this slide, gives you pretty good evidence of that. It was in 1996 that prescribing of oxycodone in New York State begins to explode. And I could show you the graph for any state, and you'd see It would be like identical to this. And I could also show you other opioids. This is hydrocodone. I could show you morphine, oxymorphone, hydromorphone. You would see the same basic point -- the inflection point being 1996, the year that opioid prescribing really begins to take off. Anybody know what happened in 1996 that could have been related to this? It was the year that Purdue Pharma introduced OxyContin. And, the GAO did a report in 2003 that looked at the way in which Purdue Pharma marketed OxyContin. And what they were trying to demonstrate with this graph is that Purdue Pharma in their marketing of OxyContin spent far more than it had ever spent before in the marketing of a narcotic. By year five they were spending $30,000,000 a year in marketing their drug. 13

14 14 Now, you might look at this and you might say, well, you know, if all of that opioid prescribing exploded because of Purdue Pharma's marketing of OxyContin, well, why wasn't it just the oxycodone? OxyContin is extended release oxycodone. Why did hydrocodone go up? Why did morphine go up? And this GAO report discussed that. What they pointed out was that the bulk of what Purdue Pharma was doing, it wasn't really even direct advertising and promotion, it was sponsoring educational programs for physicians that didn't all talk specifically about OxyContin. The bulk of what they were trying to do was to get doctors to feel more comfortable with opioids as a class of medication. So they sponsored 20,000 educational programs around the country in their first 6 years. And these were the chief messages in those educational programs. Opioid addiction is rare in pain patients. The medical community was told that we had been allowing patients to suffer needlessly because of what was termed "opiophobia." That we had this irrational fear of opioids and over-blown fear of addiction. We were told that opioids are safe and effective, and that they could be easily discontinued. And for those of you who weren't around at that time, or who are not physicians, you may hear me say that the medical community was taught that opioid -- that we shouldn't worry about addiction. What you have to understand is that the messaging was very compelling. And the way they really convinced us that opioids were not addictive was by using sort of a half truth. What they told us was that we were making this mistake of confusing physical dependence with addiction. Physical dependence, they said, well, that's going to happen to every patient that you put on long-term opioids. It means that they're going to feel sick if they abruptly discontinue their medicine. But that's clinically unimportant, don't worry about that, that just means don't stop it abruptly, taper the patient. Real addiction is extremely rare. And because you've been confusing physical

15 dependence, which is going happen to everybody with real addiction which is very rare, you're under prescribing opioids. And the truth is, we can be much more compassionate in our treatment of pain once you understand this distinction. Well, it's true. First of all, physical dependence is the wrong term, because the symptoms you experience when you try to come off of opioids are certainly not just physical. It's not just the flu-like illness, but very severe anxiety, a sense of impending doom like you're losing your mind, like you're going to die. It's like people will do very desperate things to maintain their opioid supply. So it's certainly physiological dependence. And it's true that physiological dependence and addiction are not the same thing. But the reason that opioids are so highly addictive is because of that physiological dependence, that very strong negative re-enforcement when you try to come off. And that whole notion that patients can be easily tapered off. Totally untrue. Patients who can come off opioids easily after they've been on them a while, it's -- you know, we've just heard from Dr. Clancy about the VA's struggle to get -- to get the doses down and to try to get patients off. It's very difficult. That's why you see a proliferation -- proliferation of ultra rapid detox programs springing up where people will undergo general anesthesia just to get over the acute withdrawal. And that's the acute withdrawal. Patients who've been on opioids for a long time, when they try and come off, they're up to six months of difficulty sleeping, leg kicks in the middle of the night, irritability, depression. And even the perfect pain patient who never took an extra dose, who took their medication exactly as prescribed, never looked addicted when they want to come off and they feel awful for months, and they know in the back of their mind that all they have to do to feel better again would be to take one pill, they also have very significant cravings. Now to this whole notion that opioids were safe and effective for chronic pain. If I was one of the key opinion leaders, giving a talk on behalf of industry, at this point I might put up a video, of a patient, and you'd hear a patient telling you that, "I got my life back because of OxyContin. I was out of work for six months because I injured myself on the job, I had no income, I was miserable, and now I'm on OxyContin and I feel great, I'm back at work 15

16 16 and I just bought my kid a bicycle." And in fact the patient made that statement, "I got my life back," in an infomercial Purdue Pharma, would ultimately lose his life because of his OxyContin use. But what we now know especially with data that's come from the Workers' Comp industry is if you treat an injured worker's chronic pain with long-term opioids, that worker is far less likely to ever go back to work again compared to any other intervention you could have offered them for their chronic pain. The Federal AHRQ just put out a report about four or five months ago, an evidence-based review of opioids for chronic pain, and the conclusion was we don't have a single shred of evidence that opioids are effective for chronic pain when used long-term, but we have overwhelming evidence of the risks. And in fact, we've got evidence that opioids can make pain worse. It's a phenomenon called "hyperalgesia." It wasn't just the advertising and the education, but really a brilliant campaign that Purdue Pharma and ultimately other opioid manufacturers launched. And I will say many of the people involved in this campaign, I think many were well-intentioned. They really truly bought into this notion that we didn't have to worry about addiction, and that opioids are this gift from mother nature, and we're allowing patients to suffer needlessly because we don't understand how helpful they are. And unfortunately, I think many of these individuals who led this campaign, who may have meant well, I think had they not been so well reimbursed from industry for giving these talks, they might have figured out sooner that what they were saying made no sense. The statistic you heard over and over again was 'much less than 1% of patients will get addicted to opioids.' If you were reading your textbook or a journal article, you would come across that

17 17 statistic, that much less than one percent will get addicted. And you're thinking', does that really make sense? So you go to the back of the chapter in the textbook. What you would see is in the back of the chapter, addiction rare in patients treated with narcotics in the New England Journal of Medicine That's the reference supporting this 'much less than one percent.' And you may go to PubMed and try to pull it up. You're not going to get anything. So old. It's No abstract comes up. And -- well, New England Journal of Medicine, that's our best journal. And the title sounds pretty good, so you might move on. You might say, okay, well maybe it's true. But if you said I'm not buying it, I want to see what they did in the study, and by the way, the press was referring to this as a landmark study that proved we didn't need to worry about addiction. So you say, I really want to see what they did in this study. So you make your way to the medical library. You pull out the 1980 volume of the New England Journal of Medicine, and open it up to see what they did. What you would find out was that what everybody was referencing wasn't actually a Journal article. It was this. A oneparagraph letter to the editor describing chart reviews of about 12,000 patients in which they only found four charts where a nurse or a doctor had written into the chart that a patient who had been given morphine or Demerol suddenly appeared drug seeking. This of course would tell you nothing about the risk of addiction when patients are put on long-term opioids.

18 So, fortunately our top medical journals all have been putting out papers and editorials with the message that when you treat chronic pain with long-term opioids, you are more likely to hurt your patients than help them. And in fact, the medical community has really helped usher in a public health crisis by over-prescribing opioids. From the very beginning, had the FDA said to Purdue Pharma, when they released OxyContin, 'great, you've got extended release oxycodone, you can market this, to the palliative care doc, the hospice, but you can't market this to the family doc." Had they done that, I don't think we would have this epidemic, today had they properly enforced laws that say that drug companies can only promote products for conditions where the benefits will outweigh the risks. They The effort paid off. By 2000, Purdue Pharma was bringing in over $1,000,000,000 on OxyContin. That's how you define a blockbuster drug. So they managed to take a drug that would have been appropriately prescribed in palliative care, where, you know, you don't get a blockbuster drug for palliative care medicine. Cancer patients at the end of life there aren't that many and they won't be on your drug for very long. But when you convince the medical community to use your drug for common chronic conditions, and it's a very difficult medicine to ever come off, that is a pretty good formula for creating a blockbuster. 18

19 19 didn't do that. And in fact, they actually went in the opposite direction. In private meetings with the industry they changed the rules on the way in which analgesics were approved to make it easier for drug companies to get their opioids on the market. So we start with OxyContin, and we wound up with Avinza and Embeda and Targiniq and Zohydro and Opana, and the steady stream of opioids. And with the release of each new opioid, a sales force out there in doctors' offices trying to recoup the investment it took to bring that product to market by encouraging more prescribing. How do we bring this epidemic under control? I went to great lengths to describe this as an epidemic of opioid addiction. And I understand addiction to be a disease, and I think if you frame this as a disease epidemic, what you need to do about this problem is the same thing that you would really do for just about any disease epidemic. How do you bring an Ebola epidemic under control? You contain it. And you see that people who have Ebola are treated so that it doesn't kill them. You prevent new cases of the disease. Same thing for measles or any disease epidemic. You prevent new cases of the disease and you see that people who have the disease have access to effective treatment.

20 20 Same thing with addiction. To prevent opioid addiction, we really need to see that doctors and dentists prescribe more cautiously. And of course, we have to see that people who are opioid addicted are able to access effective treatment. Why haven't we done this? Why haven't we really made a dent in this problem even though the strategies for controlling it are pretty straightforward? Well, the industry has really framed this issue for policy makers in this way, and this was a slide shown at an FDA meeting. I was at that FDA meeting on behalf of PROP making the case to the FDA that Vicodin should be put into the proper category, Schedule II. And this was someone giving a talk for an industry funded organization, telling the policy makers if you put Vicodin into the correct category, you're going to be penalizing this poor pain patient for the bad behavior of the drug abusers. And when you actually look at who's dying of opioid overdoses, it's the age group where overdosed deaths are most common, from 45 to 54 year olds. It's people who are getting pills prescribed to them for pain where we see the most opioid overdoses. Recreational use is most common in young people.

21 So PROP has been saying we don't have these two distinct groups, there's a tremendous amount of overlap, and that 63 percent of pain patients acknowledge using opioids for purposes of other than pain. Thirty-five percent meet criteria for an opioid use disorder. 21 And then in a study that was done in Utah where they looked at everybody who died of an opioid overdose, and in a single year there were about 300 deaths, 92 percent of the patients who had died of an opioid overdose were receiving legitimate opioid prescriptions for chronic pain. Family members felt that their deceased love ones were also addicted, but they were getting prescriptions for chronic pain. In summary, the United States is in the midst of a severe epidemic of opioid addiction that's been caused by the over prescribing of opioids. To bring this epidemic under control, we need to prevent new cases of addiction by getting doctors and dentists to prescribe more cautiously. And we have to see that people who are suffering the disease of opioid addiction are able to access effective treatment so the disease doesn't kill them. Thank you.

22 22 Transcripts were provided by The Barry A. Cohen Legal Team. For other talks from the 2015 PharmedOut conference on The Real Risks of Rx Drugs, see pharmedout.org/the-real-risks-of-rx-drugs.html. PharmedOut is a Georgetown University Medical Center project that advances evidence-based prescribing and educates healthcare professionals about pharmaceutical marketing practices. Find us at on twitter, Facebook.com/PharmedOUT.