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Published Online: 22 May 2010

New Opioids: Expensive Distractions or Important Additions to Practice?

Publication: Journal of Palliative Medicine
Volume 13, Issue Number 5
Charles F. von Gunten, M.D., Ph.D. (Moderator): So what do you all think about the new fentanyl products that have just come onto the market?
Russell K. Portenoy, M.D.: I have been involved in doing a lot of the studies with the new rapid-onset fentanyl formulations, including the very first one that was on the market, oral transmucosal fentanyl citrate. These formulations have all been developed in response to the view that breakthrough pain is an unmet need largely because the time course of a typical breakthrough pain is much shorter than the time-action relationship of a typical oral short-acting drug like oxycodone or morphine.
The vast majority of breakthrough pain, when evaluated in these epidemiologic studies, last less than 1 hour and have a time to maximum intensity of 10 minutes or less. When you compare that to the time-action relationship of an oral drug like morphine, you can see that there is a mismatch.
Oral transmucosal fentanyl was commercially successful. The second formulation, fentanyl buccal citrate, has also been successful for the pharmaceutical company. This success has induced other companies to formulate new products and get them on the market.
The Holy Grail with these drugs has been to try to have a time-action relationship that almost approximates an intravenous bolus, with the goal of translating a rapid effect into clinical benefit by addressing the mismatch I mentioned.
Interestingly, there has been very, very little research comparing the standard oral agents, like morphine or oxycodone, with any of the rapid-onset fentanyl formulations. Although the very few studies that have been done have had methodological concerns, they have found greater satisfaction and greater pain control with the fentanyl formulations. This cannot be viewed as definitive, however, because of the methodological issues and the need for replication in broader clinical populations and real world settings.
Right now on the market we have the oral transmucosal fentanyl citrate, the fentanyl buccal tablet, and the new bioerodible mucoadhesive patch, which just got approved. Coming on the market in relatively short order will be a sublingual dissolvable tablet, intranasal formulations, and possibly aerosolized formulations that will be inhaled. These drugs all will have company-initiated Risk Evaluation and Mitigation Strategies (REMS), which the U.S. Food and Drug Administration has been required by law to put into place. In the case of the patch and with others coming, these REMS programs appear to add some burden to doctors to make sure that they are aware of risks, including drug abuse and unintentional overdose, and the management guidelines to minimize them.
Doctors are going to have to get used to the concept of REMS and be willing to spend an extra few minutes to review guidelines, document that they are knowledgeable about the risks, and be entered into a registry. To the extent that REMS affects the newer rapid onset fentanyl formulations before affecting other opioid formulations, they may slow down the uptake of the new products as they come on the market.
Eduardo Bruera, M.D.: I rarely use any of these formulations. There is no real comparison with the state of the art, just an oral breakthrough or subcutaneous breakthrough. The vast majority of patients respond quite well to the usual breakthrough dose. I think part of the problem is a problem with definition of what breakthrough pain is. When Russ and Neil Hagen worked on the definition of breakthrough pain many years ago, they defined a very excruciating episode during otherwise very good pain control. It seemed clinically that poorly managed breakthrough pain was a rather rare problem.
After these agents emerged, breakthrough pain suddenly became a very common syndrome because the bar was lowered for what constituted breakthrough pain. So the concept of incident severe pain as a poor prognostic feature was replaced by the concept of needing extra opioids to work fast. I think it is hurting our understanding of where these formulations might be particularly effective. I would love to see studies comparing the effect of these agents with standard therapy, perhaps in patients who are particularly refractory to the traditional oral or subcutaneous agents.
I am also a little bit worried about the lack of vigilance by the FDA regarding the potential for these agents to induce more serious side effects immediately after readministration, and also about the addictive potential of these agents that, to my knowledge, has not been a major request as part of putting these agents in the market. So I really think that they may have dropped the ball a little bit on vigilance. It will not be very common that I will use any of these agents until we have better evidence of who they are really capable of helping, and also a better idea of how toxic these agents really are soon after the peak level. What do you do about driving, being active, falls, and the addictive issues?
Charles F. von Gunten, M.D., Ph.D.: Eduardo, are you thinking that the big trouble with addictive drugs are those with fast onset and fast offset?
Eduardo Bruera, M.D.: Absolutely. We know that that is exactly what people who have an addiction problem will do to an extended-release formulation: they will attempt to modify the agent so that they get the fastest possible delivery.
Rosene D. Pirrello, R.Ph.: The information published with the products themselves makes me think these new formulations may not be that different from standard opioids. For example, Onsolis (Meda Pharmaceuticals, Somerset, NJ), the recently approved bioerodible mucoadhesive patch, is labeled as having a Cmax of 1 hour, which would be similar to the other opioids that we use. The Fentora labeling (buccal tablet; Cephalon, Inc., Frazer, PA) is Cmax of approximately 1 hour; that is their wording—again, not so different.
The one concern I have from the REMS standpoint is that the company producing the Onsolis product has a limited distribution channel, which requires a lot of certification and documentation from physicians, and then requires patients to register and get the drugs from a particular group of pharmacies, or a pharmacy national network rather than being individually available.
My last concern is that they are very, very expensive compared to the other drugs with which we typically manage breakthrough pain; there does not seem to be a clear advantage.
Russell K. Portenoy, M.D.: I would like to emphasize a couple of points about addictive potential. For the average prescriber, this issue always needs to be clarified and the risk in relation to the overall population needs to be a focus of the discussion.
There is a very high likelihood that patients who are biologically predisposed to addictive disease would express high “liking” of fentanyl formulations that have a rapid onset. So there is indeed a clear concern that these drugs may be “gateway drugs” that drive an addictive pattern of use in predisposed people who try them, either in the medical context or recreationally. They may unmask addiction in patients who have the endogenous substrate to develop this disease, or may drive relapse in patients who are in recovery. They may be attractive enough to the addict community that diversion could be a growing concern.
We do not know if any of these concerns exist to a greater extent with these agents than with other prescription opioids, but there is reason for concern of course. Until they become more widely used, there will not be enough experience with them to actually see any blip in the national data that is kept about abuse liability.
Like all other opioid drugs, risk must be assumed to exist and risk management should be viewed as a best practice whenever they are prescribed, including prescription to populations with advanced illness. This always begins with risk assessment and stratification. If a patient is older and has no personal or family history of addictive disease, and no serious psychiatric pathology, the likelihood that they are biologically predisposed is low, and so the risk is probably low.
The much greater concern about unmasking addiction or relapse is in the nonmalignant pain population, where 90% of the use of oral transmucosal fentanyl occurs. Concern is greater in this heterogeneous population not because serious illness protects the patient or the prescriber from drug abuse, but because the risk factors for addiction or abuse—such as psychiatric disease, younger age, social cuing and others—are more prevalent.
I think it is a really challenging time now for the pharmaceutical industry because they had no guidelines from the FDA about what REMS should look like except for some broad requirements. The FDA won't finally get around to putting detailed regulations out until, perhaps, a year from now.
The first company-specific REMS that was developed for an existing product, the fentanyl buccal tablet, is extremely rigid. The newer REMS that is associated with the mucosal patch seems less rigid, but still requires use of a special pharmacy. Although it is simpler for a physician to register and document knowledge of toxicity, there is potential for prescription delays related to the use of a central pharmacy.
Physicians should not assume that REMS means high burden or high time, but instead, each physician needs to determine what a specific REMS requires. There will be an effort to make them less burdensome over time.
Since the patch Onsolis came on the market, my understanding is that the number of physicians who have registered has actually been above what the company had originally anticipated, suggesting that their educational program to get people to register is being successful, even though you would think that most physicians would balk at having to complete a short test and read material. But the way they set it up, which involves help by company representatives who come into the doctors' offices with a computer for immediate registration, seems to have provided education in a way that physicians have found acceptable.
Charles F. von Gunten, M.D., Ph.D.: Interesting. It makes me think of the general predilection of doctors to like to try anything that is new. It is boring to just prescribe the same stuff over and over. Eduardo, you were talking about the tried and true, but, you know, this is 2010. We should be doing something new!
Russell K. Portenoy, M.D.: I do agree. And I do not want to leave the readers of this roundtable discussion with an overall negative view about these drugs. Those in the pain community who have used them do appreciate that the more rapid onset seems to have real value for some patients. Irrespective of the Cmax, clinical trials show that pain relief separates from placebo reliably after 15 to 30 minutes, and even faster for the newer formulations, the ones that are not yet on the market. One of the intranasal formulations, for example, can show efficacy that separates from placebo after just 5 minutes. Most patients presumably won't get adequate relief this fast, of course, and the findings from placebo-controlled efficacy trials should not be interpreted to mean “effectiveness” in practice, but a very rapid onset of relief does appear to be possible with these drugs, and the patients who do get prompt pain relief may be grateful for the opportunity. The bottom line is that the rapid onset formulations probably do provide some patients with meaningful benefit relative to that which can be obtained from the usual short-acting oral drugs like morphine.
The cost is an impediment of course, as is the reality that we have very limited experience with these formulations in populations with pain from advanced cancer or other illnesses. Without this experience, it is difficult to predict risk. As Eduardo indicated, there may be a risks of falls that has not been seen in either the clinical trials or experience in the noncancer pain populations.
But having said that, the drugs are on the market and more are coming. For people with breakthrough pain, particularly rapid onset pain, they represent another avenue for treatment, and it may be worthwhile to consider them.
Rosene D. Pirrello, R.Ph.: I think we should be encouraging the companies to do some studies against our traditional breakthrough medications. Of course one would expect onset of a drug to be faster than placebo. We need comparisons with what we already use. I am just curious if the other participants have ever just used fentanyl formulated for injections buccally.
Russell K. Portenoy, M.D.: Yes, I have prescribed that several times in the past and it works. However, the kinetics of swallowed fentanyl are much slower in onset than the kinetics of transmucosally absorbed fentanyl. So if you put a liquid under the tongue, an indeterminate amount gets swallowed with each dose, so the area under the curve of that dose and the shape of that curve will vary dose to dose, depending on how much people swallow.
Rosene D. Pirrello, R.Ph.: Right. Is that similar to the original fentanyl lozenge, where about 25% is absorbed in the mouth and variable estimates from what is swallowed?
Russell K. Portenoy, M.D.: That is right.
Charles F. von Gunten, M.D., Ph.D.: Are you advocating using injectable fentanyl: Just asking the pharmacy to dispense it as a liquid that someone would take sublingually or swallow is an alternative?
Rosene D. Pirrello, R.Ph.: With an oral dose syringe, as an alternative, yes.
Charles F. von Gunten, M.D., Ph.D.: Eduardo, any experience?
Eduardo Bruera, M.D.: No. Unfortunately, we do not.
Charles F. von Gunten, M.D., Ph.D.: Because that is cheap, right?
Rosene D. Pirrello, R.Ph.: Extremely. I think it would end up being comparable to our customary generic oral medications used for breakthrough pain, actually. Although fentanyl transdermal is very expensive, if one used 50 mL of 50 μg/mL fentanyl for $2 per vial buccally, it is many more doses on a potency basis.
Eduardo Bruera, M.D.: I think the comments are wonderful. We do need nonindustry-sponsored trials to help us where the cost of these agents is becoming a serious problem. In the Houston area, the number of patients who just cannot afford their copay on these agents is large. Let us not talk about the ones who have no insurance. Every single week we find a large number of patients who have difficulty acquiring their opioid analgesics, and we frequently have to change the type of opioid due to financial concerns. So conducting trials that would help us better understand the role of low-cost breakthrough medication would be exciting.
Charles F. von Gunten, M.D., Ph.D.: I want us then to pivot to another pure agonist opioid that has recently come to market, which is oxymorphone. What are your thoughts about that one?
Rosene D. Pirrello, R.Ph.: I will start. We do not have any experience with it yet, because in general when new drugs come to market we usually wait and see—which is what we did with the extended-release hydromorphone. So at the time that they pulled the Palladone product, we were fortunate enough to have no patients on it.
But from what I have read about it, the oral-to-parenteral ratio is somewhat variable person to person, more so than you would see with morphine or even oxycodone. This is because there is a variable first-pass effect among individuals. So that is just one thing. Right now, they have only released the oral route, immediate release and extended release, but if they go on to a parenteral dosage form, that would be a concern.
Also, compared to what we currently have, it is also very expensive. It does have a little bit longer half-life, so you could dose every 6 hours rather than every 4 hours. So that may be an advantage.
Finally, it has a little more delta activity on the opioid receptors than we are used to, so that might be of interest as well.
Russell K. Portenoy, M.D.: We have quite a bit of experience with this drug. Oxymorphone injectable has been on the market for a long time. I used it 20 years ago.
Rosene D. Pirrello, R.Ph.: Oh, I had seen it 20 years ago, but it was not there today when I looked.
Russell K. Portenoy, M.D.: There have been availability issues with it, because we have also seen it disappear off our hospital formulary and then come back. The point is that the molecule itself is not unfamiliar. Plus, of course, oxymorphone rectal suppositories have been out there for a very long time, so there are many who have experience with oxymorphone that way.
Oxymorphone has come on the market as both an extended-release, which is a Q12 product, and the immediate-release, which has a similar kinetics as morphine. The company that markets this has not focused on trying to really identify any systematic advantages over the other available oral opioids. There is some early literature to suggest that oxymorphone produces less itch than morphine, and the company probably would have been wise to do systematic studies of pruritus related to opioid administration in an effort to identify a difference between oxymorphone and oxycodone or morphine. To my knowledge, this was not done, however, and the drug came on the market as just another pure mu agonist in an extended-release formulation.
So the good news, of course, is that given the tremendous variation within an individual in terms of the responsiveness to different opioids, it is always, in my view, very favorable to have available a new choice. We should feel fortunate that we have all of these drugs on the market in the United States, notwithstanding the issue of cost and insurance coverage, which makes it difficult sometimes to rotate from one drug to another. The reality is that the more we have on the market, the more likely we would be able to identify through opioid rotation the drug that has the most favorable balance between analgesia and side effects.
The new oxymorphone formulations have been used a lot by my colleagues here, and we have not encountered any problems related to variation that seems to be greater than any of the other drugs. There is just so much variation anyway in the kinetics of opioids that that probably is more a class issue than any specific drug.
Rosene D. Pirrello, R.Ph.: Russ, may I ask what you are using, then, as your standard conversion between oral and parenteral oxymorphone?
Russell K. Portenoy, M.D.: About 15 mg of oxymorphone is roughly equivalent to about 30 mg of oral morphine or 10 mg of parenteral morphine, which is roughly equivalent to about 1 mg of parenteral oxymorphone.
Rosene D. Pirrello, R.Ph.: That I am comfortable with. What I am talking about is between oral oxymorphone and parenteral oxymorphone.
Russell K. Portenoy, M.D.: We have no experience taking a patient who was on oral oxymorphone and changing to subcutaneous infusion. But if we were given the opportunity to do that, we probably would do the conversion of 1 mg parenterally to about 15 mg orally.
Eduardo Bruera, M.D.: We have also limited experience with the exception of the previous experience we had with the immediate-release formulations that were available. I think, in general, oxymorphone is one more mu agonist.
It is fascinating to me how we learn about new agents. Before, I remember, when a new opioid became available, any analgesic, or even adjuvant drugs, there usually were a couple of papers already published in the public domain. We knew much more about the agent before it came to market.
But nowadays—I learned that oxymorphone was on the market when I received for the first time a patient on it. I read a lot about pain, about painkillers and so on. So it was concerning to me that the literature was not very much. Then I started reading about it, and I am also concerned—as I was concerned for the fentanyl product—that I think the FDA also, again, seems to be consistently dropping the ball on being vigilant about new agents.
It would be a very useful piece of information not only to detect, as Russ was saying, potential advantages in terms of side effects, but to much better establish what are these agents useful for, and the long-term problems. What we find a lot with these agents is that the problems seem to happen once they are on the market, once they are being used chronically.
So I think it is very prudent with any new agent these days to remember that FDA approval does not mean that the drug is necessarily a very safe agent. It means that it has gone through some level of scrutiny. It is good to know what type of studies were done, even though the drug may be approved. I think it is very useful to be cautious and to take some time to see how the drug behaves once it is in phase IV, when it is on the market, and then make up our own minds about what role is this agent going to have for us.
There is no doubt that having different agents is generally attractive, generally useful, but it has been around for a while, and I have to say that when I need mu receptor agonists, I do have quite an array of them, and so far it has not been a major need.
Rosene D. Pirrello, R.Ph.: Just one comment that the readers might be interested in with oxymorphone is the “oxy” beginning makes them think it is more like oxycodone, but in reality it is more like hydromorphone in terms of its structure.
Russell K. Portenoy, M.D.: But I would reiterate that these similarities and differences among the pure mu agonist drugs appear to be far less relevant than the individual variation observed when patients are switched from one to another and to another. Given this variation in response to these drugs, it is very difficult to pick up any systematic drug-specific effects.
Rosene D. Pirrello, R.Ph.: Yet I was interested in your comment that it seems to have less itch, because I usually associate the less itch with kappa agonism, which is higher in oxycodone and relatively low in oxymorphone. Do you have any theory of why the oxymorphone also would have lower itch?
Russell K. Portenoy, M.D.: No. Although there are some empirical data suggesting that oxymorphone and fentanyl are relatively less likely to produce itch than morphine specifically, I am not aware that comparative trials with the kappa agonists have been done. In clinical practice, itch as a challenging problem during long-term therapy is very uncommon. One would need a huge study with many patients to see a difference.
When we are teaching about opioid therapy, we tend to focus on these differences that have been identified in very carefully done research in highly selected patients. But in the clinic, trying to treat patients who have advanced illness and severe pain, the best thing is to pick what you are comfortable with, what is the least costly for the patients, what is convenient and in terms of dosing is going to lead to the likelihood of good adherence with the therapy. Then, after titrating and judging that balance between pain relief and side effects, be prepared to rotate. That is the only approach to me that makes sense, given how much variation there is in the response to these drugs.
Charles F. von Gunten, M.D., Ph.D.: I wanted to turn to another new opioid that is on the market, buprenorphine. It is available alone, and it is also available combined with naloxone. Aside from its uses to treat opioid-dependence, which I think is sort of outside of our focus here, but in the management of pain in patients we see in palliative medicine, what role do you all see?
Russell K. Portenoy, M.D.: We have been very involved here in trying to figure that out. We have a grant to try to develop a workable methodology for switching patients who are taking other opioids to buprenorphine in a way that is both safe and likely to work quickly. Buprenorphine has several characteristics that might suggest that its role in pain management, at least in populations with advanced illness, might be limited. Yet, there is a large experience with the buprenorphine patch in Europe and some off-label use of the sublingual tablet both there and in the U.S., and this experience suggests that there may be role for it.
Among the characteristics I am talking about is the potential to induce withdrawal when administering buprenorphine to a patient who is already physically dependent on a pure mu agonist. Buprenorphine is a partial agonist with a very high affinity for the mu receptor, and it can displace pure mu agonists off the receptor and induce withdrawal. Clinicians must be aware of this potential for the emergence of potentially serious withdrawal when the drug is used for pain. Anybody who is taking a pure mu agonist is at risk, and so there has to be a protocol developed so that the drug is initiated in a way to minimize that risk.
We have developed that kind of a protocol, which is adapted from the protocol used by our colleagues in addiction medicine. The drug is started when the patient is just beginning to experience withdrawal after stopping the existing pure mu agonist. The paradox is that buprenorphine will block withdrawal that is already occurring, even as it has the potential to induce withdrawal if given to a patient who is otherwise stable but physically dependent on a pure mu agonist. A low sublingual dose is started and then carefully titrated. The question is whether the pain can be adequately controlled during that titration period when the induction with buprenorphine is taking place. And whether withdrawal can be treated or prevented, especially if patients have been taking a relatively high dose of a pure mu agonist. We do not know the answers to these questions yet, and at this point, it is probably safest to consider the use of sublingual buprenorphine for pain only in patients who are taking modest doses of a pure mu agonist, and only if the prescriber knows about the induction approach.
Another significant impediment is that the drug has this characteristic of binding to the opioid receptor extremely tightly and does not get displaced easily by an antagonist, so that patients who do get into trouble with the drug are difficult to treat with naloxone. It takes high doses and a long period of time, so there is this concern that might be an impediment in the medically ill particularly.
The third characteristic is that as a partial agonist, the drug should have a ceiling effect for analgesia. Clearly, in the context of chronic pain associated with progressive illness, there is a reasonable likelihood that you would need to titrate the dose higher and higher, and ultimately you reach a ceiling associated with partial agonism at the receptor. So that is another potential important characteristic.
On the plus side, there is a ceiling effect of respiratory depression, and so it might be a bit safer to titrate people who are predisposed to respiratory problems associated with the opioid.
Putting this all together is challenging, and it is likely that buprenorphine is never going to be a preferred drug for treating patients with chronic pain associated with serious illness. We need more experience with it and, of course, studies that more rigorously evaluate benefit and risk.
Nonetheless, it is important to say that the experience with the patch in Europe appears very positive and our European colleagues who use this drug do not seem bothered by the development of a ceiling effect to analgesia. The emergence of an abstinence syndrome with the induction can be managed, as it is when the drug is used in addiction medicine, and there are experienced people who say that as long as you start very low and titrate cautiously, the vast majority of patients do okay. Clearly, when care is taken with titration, the concern about the high affinity for the receptor and the difficulty with reversal by naloxone is not so great because overdose is so unlikely.
In short, buprenorphine poses a unique pharmacology compared to what we are used to, which may have promise for some patients, but in the absence of clinical experience, and with very few studies, it does not, and should not, play a significant clinical role right now. It has the potential to become bigger, particularly when the patch becomes available in the United States, and it might be considered now in selected patients, particularly those who raise concerns about respiratory compromise and are not on high doses of anything else.
Eduardo Bruera, M.D.: I am delighted to hear that there is work being done by Russ and his team on this agent. It is a drug that has been around for a long time, and I remember we used to have these agents available in Canada in a sublingual preparation, and it basically has become a very, very commonly used agent in Europe, particularly I was learning yesterday from Sebastiano Mercadante that it was 70% of the prescriptions in Italy.
Basically, there is no doubt that that is predominantly a promotion success. The Italians or the Europeans, who have conducted this work, apparently do not report serious problems when they rotate patients exposed to a significantly high dose of a mu agonist to buprenorphine, but there is no documentation of that.
What we know is that the European—and particularly the Italian—experience is not going to be relevant for the American population because the total dose of opioids used by Italian patients before death is much smaller, I would say in the area of one-fourth of the dose that is used in the United States. That is partially because there is a late start of the opioid by either palliative care doctors or pain specialists. So patients are not escalating dose because they are exposed to opioid analgesics much later in the particular illnesses.
Therefore, I doubt that the experience they quote with the rotation from morphine or any other mu agonist to buprenorphine is going to be valuable, because I would suspect that the dose of strong opioid they were receiving was minimal. So the agent has been quite successful in sales, but the data backing up its use are limited; we need to learn what role it is going to have.
My personal bias, based on the experience I had in Canada and the questions raised by Russ, is to be reluctant at this point to give it the same role as I would give oxycodone, hydromorphone, morphine and any other mu agonist until we understand much better the serious risks brought by rotation to this agent and have empirical evidence of who is possibly safe and who could get hurt.
Russell K. Portenoy, M.D.: The government requires that prescribers of buprenorphine for the management of addictive disease, whether it is to “detoxify” patients who are taking opioids or as maintenance, must have specific training and indicate on the prescription that the drug is being used for this purpose; this is done by putting an “X” next to the DEA registration number. When the drug is used off label for pain, this is not required.
Charles F. von Gunten, M.D., Ph.D.: I also wanted to turn to the new morphine products that contain, in the same pill, antagonists like the morphine-naltrexone product. What thoughts do you all have?
Russell K. Portenoy, M.D.: This is very interesting pharmacology, which is generically called the so-called abuse-deterrent formulations. Importantly, however, you will never see the FDA allowing this labeling, because there is no evidence yet that they actually deter any abuse. Drugs with this intent come in two broad categories. The one you mentioned is the so-called chemical type. There are a variety of different subtypes in which different drugs are mixed together in order to produce a situation that discourages individuals from grinding and injecting or snorting the drug. The other type is a physical type, in which a drug is made in a way that is difficult to crush or dissolve.
The specific drug you are talking about, which is now on the market, is called Embeda (King Pharmaceuticals, Bristol, TN), and contains morphine combined with small pellets of naltrexone. If the patient takes it orally, the naltrexone is not absorbed. If the pill is crushed for injection or snorting, the antagonist is active, and the effect of the morphine is eliminated.
The first mechanical abuse-deterrent formulation coming on the market is called Remoxy, which is a formulation of oxycodone. The pill cannot be crushed or dissolved, when it is swallowed, it releases the drug.
The key take-home message with these abuse-deterrent formulations is that they are really intended to try to reduce the risk to the public health, and they are unlikely to have any benefits specifically for the individual patient. The individual patient who engages in nonadherence behaviors is typically doing things like taking more drug than prescribed, doctor shopping, engaging in problematic behaviors other than grinding it up and injecting it. That kind of phenomenon in the clinic happens rarely, and the far more common kinds of nonadherence problems–or aberrant drug-related behaviors—do not involve adulteration of the prescribed table. What these drugs would do is reduce unintentional overdose if the drug is stolen or somehow gets into the hands of a substance abuser who wants to take the oral formulation, grind it up and snort it or inject it, and it also may make the drug less attractive to the addict community. If it is less attractive, it might be diverted less.
My own view about this is that prescribing an abuse-deterrent formulation in an effort to protect public health is a good thing as long as it does not add to the cost or burden to the patient who needs it. But obviously, time will tell whether they accomplish anything or if in fact whether the cost structure surrounding these drugs even allows us to use them widely.
Charles F. von Gunten, M.D., Ph.D.: When you were describing these, I was thinking of the patients we have in home hospice care where the patient is not the issue, it is family who may be diverting or using or whatever. If one were very explicit with the family, that might then permit the patient just to keep getting it on schedule. Would that be an example where an individual and not a public health issue, would benefit?
Russell K. Portenoy, M.D.: Yeah, absolutely. There are data now to show that in nonpalliative care scenarios, where prescription drug abuse is occurring with increasing frequency, about two thirds of the time the prescription drugs that are being abused are being obtained from friends or relatives. This is obviously partly a problem of theft from patients. Grandma has drugs, and the grandkids come in and take some out of the medicine chest and then to a party. So the scenario that you pointed out is probably very important in terms of its public health implications, and the use of these drugs may be helpful in this regard.
Rosene D. Pirrello, R.Ph.: I want to speculate about the cost. In the case of morphine, no, I do not think it would be comparable, because the current sustained-release compounds are inexpensive. But in the case of oxycodone, where the company has maintained the proprietary right for the extended-release, the new product that he mentioned might be able to replace the current extended release oxycodone if they price it right. I think people would really jump on that, because there is so much concern about OxyContin (Purdue Pharma, Stamford, CT) inappropriate use right now.
Eduardo Bruera, M.D.: How are we going to pay for all of these? We are having difficulty providing the common mu agonists to a significant proportion of our patients, and in a global scale, the problem is enormous. The vast majority of patients die of cancer without having ever received a single dose of an opioid analgesic after more than 210 years after we developed morphine. So we do have a problem of access that is beginning to be much, much less regulation related and much more cost related.
So within that context, one of the concerns of these agents is going to be that if the cheap drugs made by generics are not going to be able to come out with REMS and these abuse-mitigation drugs become the state of the art and replace cheaper opioids, one could see that we are going to face a scenario such as the oncology targeted therapy scenario in which, with very limited increase in survival for very common solid tumors, one can see an increase in cost that can be tenfold in the treatment.
So the question is going to be, how are we going to appropriately define the balance between the potential for the agents that are coming up and how are we going to demand from the FDA that the REMS respects agents that are very cheap, such as methadone, such as immediate-release opioids, because who is going to take the effort of working on the REMS for an agent that is very, very cheap and can be produced generically by other manufacturers? I have no idea how that is going to happen.
Charles F. von Gunten, M.D., Ph.D.: I am curious if people have last thoughts?
Rosene D. Pirrello, R.Ph.: Well, I just want to really endorse Eduardo's last statement. I think that is something we have to be very careful to work with the government to ensure access at a reasonable cost.
Then the last thing I would like to say is I think this is a very interesting discussion. I enjoyed it.
Eduardo Bruera, M.D.: I rarely ever have thoughts, so what I have to say is that I am delighted to have had the chance to learn. As usual, I learned an awful lot from all of you, and it has been really fun to be part of it.
Charles F. von Gunten, M.D., Ph.D.: Russ, we will give you the last word.
Russell K. Portenoy, M.D.: I seldom stop talking, so it is good to be last. I think that there is an important take-home message, which is that the tried and true things we have had for decades in the United States are not available everywhere, and not used optimally, and that the push on the part of the pharmaceutical industry to give us novel agents may be exciting and may meet the needs of some patients, but there is still a very important challenge ahead, which is just to get what works and is cost-effective out there, used widely and effectively in the United States. This is even a greater challenge out in the rest of the world, where patients are suffering uncontrolled pain in a way that is just hard to fathom living in this country.

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Published In

cover image Journal of Palliative Medicine
Journal of Palliative Medicine
Volume 13Issue Number 5May 2010
Pages: 505 - 511
PubMed: 20406105


Published online: 22 May 2010
Published in print: May 2010
Published ahead of print: 20 April 2010


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Charles F. von Gunten
Institute for Palliative Medicine, San Diego Hospice, San Diego, California.
Eduardo Bruera
Department of Palliative Care and Rehabilitation Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, Texas.
Rosene D. Pirrello
Institute for Palliative Medicine, San Diego Hospice, San Diego, California.
Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, California.
Russell K. Portenoy
Department of Pain Medicine and Palliative Care, Beth Israel Medical Center New York, New York.
Albert Einstein College of Medicine, New York, New York.
Continuum Hospice Care, New York, New York.


Address correspondence to:Charles F. von Gunten, M.D., Ph.D.Institute for Palliative MedicineSan Diego Hospice4311 3rd AvenueSan Diego, CA 92103-1407E-mail: [email protected]

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