Selecting a Specific PAMORA for Opioid-Induced Constipation

Given the 3 available peripherally acting mu-opioid receptor antagonists for opioid-induced constipation, experts consider when to use a specific agent.

David Wang, MD: Rick, we've reviewed a bunch of data for the peripherally acting mu-opioid receptor antagonists [PAMORA] agents. It really sounds as if this has been a game changer for opioid-induced constpation [OIC]. Tell me what you think are some of the advantages and where this might fit in a workflow for managing this.

Richard Rauck, MD: I think the reality is that these drugs work against a problem that's caused by the opioid we're giving, right? We're treating an adverse effects of opioids, and that is constipation. We know it's the most common adverse effet, and it often is the most distressing one for the patient. I think the PAMORAs have worked, and what I tell my fellows again is that you're going to the source of the problem in treating it mano a mano, if you will, in how you combat it.

I think that's been the biggest rationale for it, and I think the efficacy is borne out in the clinical trials. I always say the trials are one thing. Clinicians make judgments based on their experiences and what they see in their clinics. I think the fact that these drugs have quite a robust use in the clinic supports that they're efficacious and that the patients do use them in a real-world setting. That's been our experience with it. Again, I do think the other things we've talked about, whether it's outpatient surgery centers with it. Again, I do think the other things we've talked about, whether it's outpatient surgery centers [OSCs], secretagogues, or just lifestyle changes, are important and occasionally are sufficient. For the most part, PAMORAs have been a game changer, as you said, for our patients who suffer from OIC.

David Wang, MD: Jeff, you started talking about this earlier when deciding between Relistor or the other PAMORA agents. How would you recommend we approach considering 1 drug over another in this class?

Jeffrey Fudin, BS, PharmD, DAIPM, FCCP, FASHP, FFSMB: Sure. I think first it's important to recognize that all 3 of them work well in treating opioid-induced constipation. One of the things we sometimes need to consider is what a third-party payer has on as a preferred agent. We need to be smart about how we select these. For example, if the preferred agent was Movantik, Movantik is metabolized by cytochrome P450 3A4 [CYP3A4], which we talked about, and it also depends on P-glycoprotein for absorption. It does have a contraindication for strong inhibitors of 3A4. If the patient is on itraconazole, for example, we need to be very careful and make the argument that it would not be appropriate to use Movantik, because there's a contraindication. On the other hand, if the patient was on a strong inducer, such as carbamazepine, one way to get around that would be to switch carbamazepine to oxcarbazepine. That would be one way of getting around it.

The other thing you can do is select a different PAMORA if you have that latitude. That would leave then Symproic or Relistor. Symproic also depends on 3A4 and P-glycoprotein and does not have a contraindication for 3A4 inhibitors, but it is a question in the package insert. That's going to be important. And of course, P-glycoprotein drugs for either Symproic or Movantik.

Relistor does not have any significant interactions with any of the CYP enzymes. Yes, it is in fact a substrate for CYP2D6, a weak inhibitor of 2D6. But the studies that have been done have not shown there to be any drug interactions whereby the dose would need to be adjusted. That's important. One of the things that should be considered with Relistor, however, is that if you consume a fatty meal, it can decrease absorption by 50%. Because of that, the recommendation is to dose it 30 minutes before a meal and on an empty stomach if possible.

Another consideration—particularly in the older patient, we may see this for Relistor—is that the dosage should be adjusted downward from 450 mg once a day to 150 mg once a day in patients who have a creatinine clearance of 30 or less. That's not necessarily problematic. In fact, it may be an advantage in patients who have compromised kidney function to start on a third of the dose. Likewise, if a patient is on Movantik and there's a concern because the patient is on a moderate enzyme inhibitor, then the recommendation is to start them on 12.5 mg instead of 25 mg. In summary, they all work well, but there are nuances in all of them, particularly with the pharmacokinetics that should be considered in selecting an agent.

Richard Rauck, MD: Jeff, I don't know if you would agree with this or the other panelists. One thing for me, when I'm considering these drugs as well, is if a patient got Relistor, methylnaltrexone, in the subcutaneous form—and this happens with my palliative care patients—and they come to me and they weren't started on an oral, I really like to stay with the same molecules. If they tell me the subcutaneous formulation worked, that's the time I'll push hardest on the payer if they want to try to say one versus the other. It just seems to me to make sense as a clinician. Let's not switch drugs if you had one that worked in one dosage. As we know, methylnaltrexone is the only PAMORA that comes in two dosage forms. So I think there's one consideration I give in that special class of patients.

Jeffrey Fudin, BS, PharmD, DAIPM, FCCP, FASHP, FFSMB: That can be an easier sell, I think. Saying to the patients, just to be clear, all 3 of these have a similar nucleus. From a perspective of intolerance or allergy, they should not be an issue. I don't disagree with what you said, but sometimes people will say, "I like to stay on the same drug because I know that they'll tolerate it." I don't see that as an issue so much. Again, given the interactions with some of the other agents that we don't necessarily see with methylnaltrexone, then yes, I think that it is smart to stay with the same drug if you're able to do that.

Richard Rauck, MD: Maybe it's not fair just to say on the efficacy standpoint. These drugs can reverse analgesia. I think, again, one thing for me to think about is staying with the same molecule, just so I don't possible cause them problems with the other one.