Posted by Jeff Berk, BOLT International; A couple of weeks back Pfizer recalled one of the key products that came their way via the acquisition of King Pharmaceuticals. Some lots of Embeda, an extended release “abuse resistant painkiller” did not pass stability tests. Now, Embeda won’t be available for a couple of months. I bring this topic up tonight because it gives me an excuse to share two tidbits from BOLT’s Pain Thought Leader panel, published a few months ago. The expert anesthesiologists made a few comments on Embeda (they weren’t impressed, so I’m not impressed). Then, the major part of this blog is a pretty extensive discussion that we had related to unmet needs in the pain category. The number one unmet need, and thus the one that I’ll share in this blog, relates to opioid abuse potential. So without further ado…
Embeda (morphine / naltrexone; King / Alpharma / Pfizer)
- Embeda, a morphine / naltrexone combination delivered by capsule, was approved by FDA for use as a Schedule II drug, with the label: “Embeda can be abused in a manner similar to other opioid agonists, legal or illicit. This should be considered when prescribing or dispensing Embeda in situations where the physician or pharmacist is concerned about an increased risk of misuse, abuse, or diversion.” The key point is that there was no data filed with the registration suggesting that there was evidence that Embeda is less likely to be abused than other extended-release morphine drugs. In addition, in a clinical trial, 11% of patients have naltrexone showing up in their blood stream. Net, Embeda is viewed as a marginal improvement over morphine alone.
“So we have Embeda we have a lot of emphasis by the vendors, manufacturers, drug companies, pharmaceutical agencies to try to develop substances which have deterrents against abuse. But that doesn’t really solve the problem because for every system there is somebody who has the wherewithal, the knowledge, the background, the training, the experience to kind of thwart the efforts at limiting the abuse potential of every agent that has ever been developed”.
“So I think that Embeda, the new morphine, is the first one of its kind and I think that you are going to see many genre of this drug coming out in the future. Is it available right now? It is available now but only in morphine. But you are saying that you should be able to put any drug into this? You should be able. The concept which was very smart was to develop a platform and from that platform basically have any opioid can be put into it. So I think that what happens is if you don’t abuse the drug it looks like morphine, smells like morphine, acts like morphine. If you abuse the formulation in any way you basically have a release of Naltrexone. Naltrexone reverses the likeability of the high. You still get a little high and because of that I think you are not going to get flagrant withdrawal, but the likeability really goes down”.
“A lot of the drugs that are going to be mixed together such as methylnaltrexone with an opioid and I believe Alpharma has come to market with this or is very close. I am not sure. I think that these agents are going to get a lot of play. They are not a major step forward but they are an improvement and I think in the near term that is what we are going to see brought to market. Will any of those get the DEA off the physician’s back? I think the ones that have methylnaltrexone with the opioid”.
Managing Opioid Abuse Potential
- The number one unmet need in the opioid space is for formulations that produce the efficacy profiles that can be obtained with fast acting narcotics but can’t produce the high that underlies the abuse potential.
- This need is applicable to both the short-term post-op patient and the long-term chronic pain patient. For chronic use the analgesic levels should be reached within an hour, last for at least 12 hours and be dosed at most twice daily. Constipation is a significant problem for chronic use.
“So in terms of the release profile I would want a narcotic that can be or has to be dosed at most twice a day which would ensure high attrition rate and compliance and the release profile would be such that analgesic levels would be reached within an hour and would be maintained for at least 12 hours. There are various compounds out there that sort of match some of these properties but that is in an ideal world. That would be a narcotic that I would want”.
- For acute pain, the time of onset has to be much faster; 5-10 minutes. Constipation is not really a concern, but respiratory depression is.
“For acute pain I see it slightly differently. For acute pain management you are much more interested in a narcotic that has a fast onset. A patient wouldn’t tolerate an hour; you would need something that is effective within 5-10 minutes typically. So you would be much more interested in an opioid in terms of the physical chemical properties it is probably different from an opioid that you would use in the chronic dosing domain. This issue of constipation is not a real big issue here. I would say in the world of anesthesiologists maybe if you take patients who are requiring opioids for several weeks that is an issue, but I don’t think it is one in the perioperative field for example. So here you would focus on narcotics that are fast onset and are safe. Here the main safety concerns are mainly respiratory depression and sedation. So people fall asleep and they are obstructing their airway, not because they are respiratory depressed but because their airway is basically collapsing. They can’t breath and they die or are risk of dying from that. So again my dream narcotic I think would be very effective but not cause respiratory depression or not as much”.
- The two approaches currently being developed are to include in the narcotic preparation an agent that produces an adverse reaction when ingested at levels above those that correlate with proper dosing of the concomitant narcotic, or an agent that increasing diminishes the high of the concomitant narcotic. Neither of these approaches address the fundamental problem, which is to not just act as a deterrent once addiction behavior has become codified in the brain, but something that minimizes that codification process in the brain in the first place. King / Alpharma’s Embeda is the first morphine based extended release product that has reduced abuse potential, but as we discuss in the mu receptor/opioid section, its added benefit is marginal. There are no oxycodone or fentanyl extended release formulations that really fit the profile above. These efforts are never going to fully deter the individual who has the knowledge, background, training and desire to thwart the efforts at limiting the abuse potential of a narcotic formulation.
“I will give you an example. I was one of the earliest advocates of using transdermal systems. I thought transdermal systems were the cat’s meow going back a long time ago, 15 years ago for example, because I thought they obviated some of the behavior. The process of people becoming habituated to medications entails not just the interaction at the receptor level on the brain, but there is a whole process that goes on where behaviors are altered. So talk about the process of becoming habituated and moving from habituation to maybe a full fledged addiction I am talking about people who then use everything on a conscious level and subconscious level to continue to process paradigms to get more medication to constantly saturate their receptors. I don’t know of any chemical that has either been developed or is in the developmental stages now which is a pure analgesic that is devoid of influencing the reward center in the brain. I don’t think it has been done. Everybody is putting stop gap measures in. They are putting in chemical measures to try to abort the adulterant process or someone crushes the chemical or there is something liberated; naltrexone, naloxone that is going to give a dysphoric effect. But there has got to be something that goes even deeper than that, something which is not just a deterrent once the behavior has become codified in the brain, something that minimizes that codification process in the brain. So if you are generally quite pessimistic about skinning that cat directly… Oh I am not pessimistic. I am an eternal optimist. I will give you an example. We have got a gulf oil spill and so now people are scurrying about to try to dig some kind of well to release the pressure off the first well. That is chasing the horse after it is already out of the barn. That is how I think some of these chemical processes are. They are put into effect after the brain chemical milieu has already been established and it is much, much harder to solve the problem that way than it would have been to be proactive and to have eliminated that potential”.
“So we have Embeda we have a lot of emphasis by the vendors, manufacturers, drug companies, pharmaceutical agencies to try to develop substances which have deterrents against abuse. But that doesn’t really solve the problem because for every system there is somebody who has the wherewithal, the knowledge, the background, the training, the experience to kind of thwart the efforts at limiting the abuse potential of every agent that has ever been developed. So what really needs to be developed is something that doesn’t process itself in the reward center in the brain. Something which is fundamentally a chemical lock and key with nociception to anti-nociception but doesn’t somehow result in a pleasurable and drug seeking behavior from the individual”.
“Anyone at any time can divert. So when you see a patient and you submit them to some type of acute trauma, which is surgery, and then you send them home with something you have no idea where that drug is going. So any opioid, whether it is used for chronic pain or whether it is used for acute pain I think can benefit from this kind of pharmacologic manipulation”.
“I think that the pipeline that is going to occur with respect to tamper-resistance opioids is the thing of the future. They are coming out with novel preparations so that either the individual who abuses a drug gets an adverse reaction or an individual who abuses an opioid gets a reduced sort of likeability to the drug. I think this is the wave of the future. I can actually see a time when the only opioids that will be available will be ones that have this kind of abuse resistant pharmacology”.
“Oxycodone in some type of sustained release formulation I think will come next. I think that the reason for that is simply because if you look at the opioid market one-third is morphine, one-third is oxycodone and another third is fentanyl. So Duragesic (fentanyl transdermal) captures that third. Oxycontin or oxycodone IR captures the other third and then morphine captures the other third. So they have got a morphine on the market now. Then they are going to go for an oxycodone extended release with some type of diversion resistant mechanism. I think that is going to actually be a fairly big seller because, at least here in Los Angeles, because I think that many more people abuse oxycodone here than abuse morphine to begin with”.
- In order to cut down the risk of addiction, the top three behaviors that need to be altered in patients who are going to be taking narcotics are smoking, other obsessive-compulsive behaviors and alcohol/substance abuse.
“I am talking about removing some of the conduct associated with people who have the predisposition for developing addictions and so forth. I am talking about taking away the behaviors because we know that behavioral constructs are underestimated when it comes to chronic use of mood altering chemicals. Give me the top three behaviors that you focus on there. Smoking, other obsessive-compulsive types of conduct and probably any previous history of either alcohol misuse or other chemical substances, even probably the pedestrian use of drugs like marijuana, which is felt to be by some of my colleagues benign but I think what it proves is a willingness to take risks and a willingness for people to do things which are culturally still considered somewhat abnormal”.
- Driven by its desire to decrease misuse of opioids by both patients and non-patients, FDA has demanded the implementation of highly intrusive REMS (Risk Evaluation and Mitigation Strategies) programs. These REMS are the first examples where FDA is imposing on patients and physicians a monitoring and compliance burden that doesn’t actually benefit the patient. Many primary care physicians are no longer going to run their own pain clinics. This has driven up patient co-pay costs and decreased convenience as they now must see specialists, even for routine prescribing. It has also had the unintended consequence of driving Pharma R&D toward tamper-resistant / abuse-resistant opioid formulations, and away from novel therapies. Panelists love the idea of a narcotic that works exactly like it’s supposed to when used as prescribed but either doesn’t work or has an adverse effect when abused. We expect that ultimately some patient will abuse one of the formulations designed to prevent abuse, be “injured”, and win a tort against the manufacturer for producing a defective product and covering up evidence that they knew the danger.
“If the patient uses the drug appropriately, it looks like the drug it is supposed to be, it acts like the drug it is supposed to be, it smells like the drug it is supposed to be”.
“A lot of the efforts of pharmaceutical companies are now going into the REMS. Are you familiar with REMS? Yes. They are really delving into REMS on the front end and back end to make a tamper-resistant product or an abuse-resistant or product theoretically. To my knowledge they are not focusing on novel medications. Not right now”.
“I think that the only way that you are going to be able to get an adverse reaction, and remember the adverse reaction agents are not on the market yet, it is only one which reduces the likeability so that you have less of a high. Number one, unless you were doing something you shouldn’t have been doing with that agent then you are not going to get the adverse reaction. So what I am hearing you say is that you have enough of the therapeutic window that as a physician you can titrate the opioid as you wish? Oh absolutely. The therapeutic window is exactly the same as any other opioids. So you are not losing or gaining any concept of therapeutic window. What you are doing is you are getting an added benefit of potentially reduced diversion. I think that I am sure that some trial lawyer somewhere is going to well this happened to and my client. Well what was he doing abusing the drug in the first place?”
- None of the opioid oral or transdermal delivery systems were thought by our panel to be notably superior to their competition, in that none have been shown to significantly decrease diversion or tampering. There may one day be a sociological study that shows that tamper resistance has a positive effect on abuse, but that day has not yet arrived. We think FDA is going to be increasingly hostile to approving new formulations that don’t prove to lower abuse in populations that are prone to abuse. See Acurox for a recent rejection.
“All opioids at one point or another in time will have some type of tamper or possibly resistant technology associated with it. I think that is the future. The platforms are being developed and I think that eventually there is going to be some sociologic study that either shows that there is or there isn’t an effect, but I think that is where people are going for the time being”.
“Of all the branded products that are coming out in terms of new formulations of oxycodone do any of them differentiate themselves? They do not. Some of the tamper resistant products by Purdue Pharmaceutical, theoretically it is going to work that someone is going to crush it and either inject it or snort it. Most people are going to take it and they are going to take the whole pill”.
“Now, I can’t say that at the present time whether there really, truly has been a reduction in diversion or reduction in tampering because we don’t have that data. But at least these are novel ideas that have the potential to reduce diversion”.
“The CDC has really given the impetus to this, and I don’t think the FDA is going to allow any other opioids on the market unless they have got some type of ingenious potentially abuse deterrent formulation. I honestly think it is going to be the wave of the future”.