William F. Peacock, MD

If you see a patient with OIC [opioid-induced constipation], this is a reasonable option to try. If it works, then it’s reasonable getting the patient on board. If they want to go home, let that happen. If it doesn’t work, then you go back to the same plan B we’ve always had, which is enemas, manual disimpaction, hospitalization, and observation. The majority of patients from the data we’ve presented will have relief and be discharged home.

In the hospital, with medicine, emergency doctors can use only the drugs that are on formulary. I can’t use anything else, not in the ER [emergency department]. I can write a prescription and discharge the patient. In this setting, if it’s not on formulary, I’m not going to have much of an effect. If a patient comes in with abdominal pain and I think it’s opioid-induced constipation, I don’t want to send them home until they feel better. If I can’t use methylnaltrexone to make them feel better, I’m not going to send them home on a pill that I haven’t even tried. The limiting factor in the house of medicine is the formulary. It controls what I can and cannot use.

What I’ve found is that it seems to be used in the majority of institutions and in those with large cancer populations in patients who are on a high amount of opioids. In places that don’t have large cancer populations, it doesn’t seem so well adapted.

What our studies have shown is that in patients receiving methylnaltrexone, about 60% will have a defecation within an hour or 2. At that point it’s a clinical decision of hospitalization or discharge, most of which will be able to be discharged. This results in a significant cost savings, about $730 for every dose used in the emergency department.

The biggest challenge for using methylnaltrexone for OIC treatment is the formulary. If it’s on formulary, then that becomes a selection choice that I can make with the patient. If it’s not on formulary, it’s an outpatient drug that’s not going to work for me in the emergency department. That’s the biggest challenge.

Videos

Dr William F. Peacock shares clinical pearls for the management of opioid-induced constipation.

Key Takeaways for OIC Management

We’ve looked at the population of patients with single-dose opioid-induced constipation therapy, and we’ve looked at the population of patients with cancers, and we’ve evaluated the health care economic implications retrospectively. The 1 piece we’re missing is a randomized prospective-controlled trial in the emergency department environment. We have studies in the non–emergency department environment. We haven’t had a solid randomized controlled trial, which is 1 thing I’m pushing for because it would close the door on this. We have what looks like a pretty effective option in the treatment of opioid-induced constipation, but ultimately we need a randomized control trial.

What you’d like to see with a quality randomized control trial is efficacy and then admission rates vs intervention vs not. You’d want to make sure the patients had a lasting benefit. How robust was this cure? Are patients who are discharged maintained as outpatients? Because if I send somebody home and they come back in 3 days, then I haven’t won. It’s just a stall. We want to make sure we’re curing their problem when they leave. This is information that’s hard to pull out of a retrospective trial. That’s the point of continuing the investigations.

An expert in emergency medicine shares his thoughts on the patient population inclusion criteria study designs when investigating treatment efficacy in patients with opioid-induced constipation.

OIC Clinical Trial Patient Population and Study Design Considerations

Trying to grade severity of OIC [opioid-induced constipation] is very difficult because this is a patient perception parameter. They can tell you, “I feel miserable on a scale of 1 to 10.” If they’re 10, that’s terrible; if they’re a 1, that’s great. But people never go to the ER [emergency department] with a 1. Everybody is more than a 5, and this is a made-up scale. I don’t think there’s an OIC scale, at least not for emergency doctors. It’s what the patient is telling you.

The population that we selected for our study was pretty diverse. It did predominantly contain patients with cancer—about 70%—but the important part is that another third of them were not. There were people with chronic back pain, chronic arthritis pain, and other reasons that people take narcotics. It’s a fairly representative population suffering from OIC that you’d see in an emergency department.

The point of picking the population and the diverse nature of this is that it can be used for real-world application. It’s not just a cancer drug. It’s not just for rheumatoid arthritis and broken bones. It’s for the full spectrum of people who will show up with the complications from an opioid.

The challenge of OIC is that our normal therapies don’t work very well. Our normal therapies include getting an enema—that’s not enjoyable, and it doesn’t work that well. You can get manually disimpacted—nobody likes that; it’s painful. Doctors and nurses have to do it but don’t like it, and it doesn’t work very well. Then you can give them something orally and wait around for 3 or 4 hours. You end up in this cycle of a bunch of stuff that doesn’t work well and is uncomfortable for everybody. A medication that could have a beneficial effect and be done in an hour or 2 is an option that we haven’t had.

Emergency doctors will be familiar with naltrexone. Naltrexone is the narcotic antagonist. You give it to them, and narcotics go away. The patient immediately goes into withdrawal if they were addicted. That’s a problem, but it’s the function. We call it Narcan-naltrexone. Methylnaltrexone is just as it sounds: they added a methyl group to it. The beauty of that is it doesn’t get into your brain, it goes to your colon. The way I think about this is your colon goes into withdrawal immediately, and you have to go to the bathroom, which normally happens with somebody who gets Narcan [naloxone], but Narcan [naloxone] goes in the brain and allows you to override the other effects of opioids. Methylnaltrexone can’t do that. It only acts peripherally. It’s 1 of the huge strengths of what we discovered in our analysis. When you give methylnaltrexone to a patient with cancer, they still have their pain relief. They don’t lose it, but their colon goes into withdrawal and they have to go to the bathroom, which is exactly the target. This is 1 of the nicest examples of designed medications I’ve ever seen. We have a medication that works really well and creates withdrawal, and we can prevent it from reversing all the effects. They maintain their pain medication effect but not their colon effect.

William F. Peacock, MD, discusses real-world implications with opioid-induced constipation and comments on unmet needs in treating patients.

Real-world Implications and Unmet Needs of OIC Management

 We did a fairly sophisticated analysis of a large database of hospitalized patients to see the economic outcome of using a PAMORA, a peripheral acting μ-receptor antagonist. In our analysis, methylnaltrexone was the most common, about 93%, but that’s just a marketplace function. We did this analysis to find out how it worked and what the economic consequences of it were. It was a health economics analysis. We took about 30,000 patients, and we did what’s called an entropy analysis. When you do this, you control for as many as 50 variables. You take the mean and the standard deviation, so that the 2 populations—those who have OIC [opioid-induced constipation] and get a PAMORA and those who don’t get the PAMORA—are matched well. We did that, and we ended up with 20,000 patients in the non-PAMORA group and 10,000 in the PAMORA group. We can compare those populations. It’s a retrospective study full of all the retrospective study concerns and limitations, but the matching process takes us into a much more sophisticated realm of understanding.

Using that entropy-controlling analysis, we were able to demonstrate that on average, for a person who had OIC and got a PAMORA, the cost savings was about $730 per dose, which is pretty phenomenal. Very few things save money like that. The function is that they stay shorter in the ER [emergency department]. They get the shot. This is a subcutaneous injection, so there’s a pill form, but the pill form isn’t an emergency doctor target. We want somebody to have a relief or not so we can make a decision. I don’t want to wait 4, 5, 6 hours. It’s a subcutaneous injection. The patient has a relief for their symptoms, and you make a decision.

This drug works in an hour or 2. When that happens, you can then decide if you can go home. If I can discharge somebody in 2 or 3 hours in the emergency department, that’s a win, as opposed to messing around with them for 6 or 8 hours. That’s a discharge. There’s huge money saved when you can discharge somebody who wasn’t getting discharged before. So you give a shot, you wait 2 hours, then they can go home. It shortens the ER length of stay; that’s a cost savings. They can go home; that’s a cost savings.

About 60% or 70% of the people who got treatment were able to be discharged, which isn’t our normal game. Historically, most patients with opioid-induced constipation come in the hospital the ER, and we do what we can do. We do manual disimpaction, we give them enemas that don’t work well. They’re not happy, and they end up getting put into observation or hospitalized. This is a way to change the trajectory for that patient. You can do something that works and send them home. That’s why it’s a cost savings of $730 per patient.

Is patient monitor follow-up required? Remember, these are patients with cancer—70% of them had cancer. The answer is yes. Monitoring and follow-up are required, not for the opioid-induced constipation but because of their underlying disease. These are fragile patients who were sick, so they’re going to follow up with their doctor no matter what, even if I don’t do anything. The methylnaltrexone doesn’t create a special scenario of monitoring or follow-up. It’s not necessary. If they had a benefit from their treatment in the emergency department and go home, they can follow up as scheduled regularly with their doctor.

One thing the emergency doctor can consider is whether to put the patient on the oral pill when they leave, and you can do that. They take it every other day, but that’s a decision to be made with the patient at the time of the visit. Once the problem is cured, you can turn that over to their doctor as an outpatient if you wanted.

For people who take narcotics, opioid-induced constipation is 1 of the most common complications. In the patients we were talking about in our analysis, it was the most common reason to come to the emergency department. About 60% of these people ended up with at least 1 visit. Some of that is a function of our analysis. We were looking for people with ER visits so we could study them. What it tells you is that opioid-induced constipation is a common problem, and it results in frequent emergency department visits.

In this study, the large analysis—the 30,000-patient evaluation—most patients are pretty sick. They’re patients who have 70% metastatic cancer, and they’re getting complicated therapies for their underlying disease. Then they’re complicated by opioid-induced constipation. This is important because this is what this population looks like. This isn’t a population of relatively healthy patients. This is the real-world population of everybody who’s coming to the emergency department with opioid-induced constipation.

There are limitations. It’s a retrospective study. As such, we had to match patients as best we could. I’ve talked about that a bit. The downside is it’s that a retrospective study. The upside is that it’s a real-world population. These are the real patients who come to the emergency department with opioid-induced constipation. A challenge in this analysis is that there’s no OIC code. I can’t look at a database and go, “Let’s pull out the OIC patients.” We had to create OIC diagnoses. The way we did that is we found people who came to the emergency department with a diagnosis of constipation or obstipation, for which there are codes, or who had a procedure—a manual disimpaction, or something of that nature, so we could track that in the medical record—and who were on a narcotic sometime in the last 6 months. We had to create the population. Then we had to have those patients who got a PAMORA vs those who didn’t. That’s how we ended up with this analysis, but that’s the big weakness in it. If there were a code, it would have been a lot easier. Without a code, we did the best we could diagnostically. That’s sort of the support as to why we still need a randomized controlled trial of patients who we’re certain of their disease and the treatment that was given.

Dr William F. Peacock provides insight on the economic burden of opioid-induced constipation management strategies, highlighting the impact of hospitalization rates and prescription costs.

William F. Peacock, MD

Articles

Latest News