MCAM Blocks Opioids Fatal Effects? – In-Depth Doctor’s Interview


Charles P. France, PhD, Professor in the Department of Pharmacology at UT Health in San Antonio, talks about a drug that could help those who are fighting opioid addiction.

What is it about these drugs that they have now that make people crazy to get their hands on them? What’s the brain doing? 

Dr. France: Well these drugs are tickling very powerful reinforcement mechanisms that are in the brain that subserve other kinds of things that are reinforcing in life whether it be food, water, alcohol, sex, or socialization. Drugs are tickling the same systems but they stimulate those systems more robustly than many other things. If you will, the term often used is that they hijack the reward system in the brain and essentially take over and supplant other kinds of reinforcers so that people seek out drugs and avoid other things that would normally be reinforcing.

I can’t imagine how frustrating that must be both in your position and for an addict to crave something that much. 

Dr. France: It’s clearly very powerful. It’s frustrating from our point of view because it’s a very difficult problem that’s been worked on for many years. It’s difficult from an addict’s point of view because it’s got a biological component to it that essentially takes over the person’s life. It’s not simply a matter of choice – it’s a matter of biology. Once those drugs take over, it’s very hard to break the habit.

You’ve got the Narcan that you can administer on the spot and it’s not all that long lasting so once it’s administered, patients can relapse while in the ER. Can you go into that a little bit? 

Dr. France: Yeah, that’s a major problem. The good news is that we have Narcan – naloxone, and it’s very effective. It rescues people from opioid overdose if given promptly. That’s the good news. The bad news is it doesn’t last very long. Its duration is about 45 minutes to an hour. Now most drugs that people take and abuse – and that they may take accidentally – have a duration that’s much longer than 45 minutes. So you’re exactly right. Someone may be rescued with a dose of naloxone and seem perfectly normal. But as the naloxone wears off and the drug effect begins to reemerge, they could then fall prey to respiratory depression and in fact die. This is a major management issue in emergency departments but also out in the public where your friends and colleagues may actually rescue with naloxone and may need multiple doses of it to keep you alive.

Then if they would relapse again, what are the symptoms? How do you know? How would you save, or re-save somebody? 

Dr. France: Well the same symptoms begin to emerge with sedation, there is a change in pupil diameters, and respiration slows down. You’re right that people in emergency departments know about this but that doesn’t mean that there’s no problem in the emergency department. There’s a very high profile case that occurred in Sacramento a couple of years ago in which individuals in the community thought that they were taking their Vicodin that they had been taking for many years. In fact, the Vicodin pills had been adulterated with Fentanyl – in some of the cases the doses of Fentanyl were four times larger than a dose that would kill an individual. The emergency department actually exhausted their supply of Naloxone trying to keep these people alive. In fact, one patient had to be put on an I.V. drip of Naloxone for nearly two days to rescue him. So it’s a challenge even in emergency departments but particularly out on the streets. There are other cases that have been in the press in which law enforcement have gone into a drug bust scene and thrown in a concussion bomb, and Fentanyl-like drugs have become aerosolized and they have ingested them and maybe had one dose of Naloxone with them. Well the one dose of Naloxone saved them for 45 minutes but they were in trouble thereafter. So the short duration of Naloxone, though it’s a very good drug, clearly limits its applicability in medicine

You and your colleagues knew a long time ago that you needed a long lasting reversal type of process or drug.  

Dr. France: We may have known it. We certainly knew that the drug was there. The demand did not seem to be as great until we got into the current opioid crisis and particularly in this third phase of the opioid crisis. You know it started with prescription opioids. It transitioned to very cheap heroin that was easily available. Now it’s Fentanyl and Fentanyl-related derivatives which are very, very inexpensive, very easy to make, and widely distributed. Enough Carfentanil, one of these derivatives that would cover a penny, would kill thousands of people. It’s incredibly potent. So the need to have more aggressive treatments for the rescue from opioid overdose has really come into focus in the last few years.

So you’re talking about people everywhere need to be concerned about those. Not just addicts and people who know addicts, but policemen, and anybody who might come into contact say with Fentanyl. 

Dr. France: Absolutely. You know one of the applications of Naloxone or Narcan-like drugs is to give it to law enforcement and, if active, military personnel, who may find themselves in harm’s way and inadvertently come upon inhalation for example of a Fentanyl-like drug.

What does it actually do when the Narcan combats the Fentanyl-like drugs? 

Dr. France: Well there are places in your brain where drugs have their effects. We call them receptors. They’re proteins, and that’s where the drugs bind. It turns out that Naloxone binds to those same places in the brain that all of the opioids bind to; including heroin, fentanyl derivatives and anything else. So they compete for the same place. and if you get enough Naloxone in there, then the fentanyl or the heroin can’t bind to the receptor.

So that drug that goes into the Narcan, is it getting in front of the fentanyl or is it fighting for position or what does it look like? 

Dr. France: They’re competing for it and the one who has the most warriors wins. That is the more drug that you have, the higher the likelihood it’s going to occupy the receptor. So one problem again with Naloxone is that you can rescue someone but if they decide to take more opioid they can surmount, they can overcome the protection that’s provided by Naloxone.

When they get the Narcan does it make them any less likely to crave the fentanyl or other opioids? 

Dr. France: No. It rescues them from overdose. So once rescued they may feel the urge to again take a drug. So once the Naloxone is gone there’s no protection and there’s no alleviation of craving.

So once the effects of the Narcan wear off, are they back to where they were or does it make them crave it even more? 

Dr. France: It would not make them crave it even more. It would precipitate some opioid withdrawal syndromes and those can be overcome with other kinds of medications but it should not make them want the drug even more.

What does an opioid withdrawal symptom look like to you? 

  1. FRANCE: It looks like a bad flu, a very bad flu, gastrointestinal distress, sweating, perhaps vomiting and diarrhea.

Let’s switch over now to the new long-lasting opioid drug, MCAM.

Dr. France:  Its real name is Methocinnamox. We call it MCAM, M-C-A-M. MCAM is very much like Naloxone. It shares a number of properties with Naloxone. It binds to those same places in the brain that we talked about and therefore it can rescue people from opioid overdose and prevent the effects of heroin and fentanyl. The difference with MCAM compared to Naloxone is that once it binds to that place in the brain it doesn’t unbind. That affords it some very nice features – for example the reemergence of opioid effects that we talked about because the short duration of action of Naloxone doesn’t occur with MCAM. A single injection of MCAM will rescue an individual from overdose and prevent them from overdosing even with very large doses of opioids for a week or longer. So patients can return to their normal lives after they’ve been rescued with an opioid without fear of them relapsing and killing themselves with another dose of drug.

So is the MCAM having an effect on the craving as well? 

Dr. France: No. It’s acting at that same receptor. The difference again is that once it binds there it doesn’t unbind. So there’s no chance for the opioid, heroin or fentanyl, to bind to that receptor.

So it doesn’t impact the craving anymore? 

Dr. France: It doesn’t impact craving. That’s not the purpose of this drug. The purpose of this drug is to rescue people from overdose and to provide extended protection so that they don’t have to be monitored by health care providers or others.

Can you describe briefly what happens when someone goes into an E.R. and 30 minutes ago they’ve had the Narcan and 30 minutes later they’re hurting again? 

Dr. France: Well when they come in intoxicated they’re likely to be heavily sedated, perhaps unconscious. The rescue with Naloxone is essentially immediate. Once it’s put up the nose within a matter of a minute or a couple of minutes the individuals rescued respiration normalizes and physiological functions return largely to normal. Sometimes there’s an exacerbation of things – irritation because of the withdrawal syndromes that occur. Depending upon the kind of opioid they’ve taken and how much they’ve taken, that withdrawal syndrome may dissipate over a few hours and the individual may be perfectly normal. On the other hand, if they have taken an unusually large amount of drug or a very potent drug, once the Naloxone wears off sedation, is going to set in again. The respiration will slow and the individual will go back into the same state in which they entered the emergency department.

In your field, how exciting is a development like this? 

Dr. France:  It’s unbelievable. It’s clearly the most exciting thing in my career. We study a lot of things that we think are important but there is a dramatic public health need out there. More than 100 people per day are dying in the U.S. from a drug overdose – most of them from opioids. This despite the fact that we have medications. We have had medications for 50 to 70 years that in some ways are very good at treating opioid overdose and opioid use disorder. It’s not just the overdose problem, it’s the opioid use disorder. You’ve probably heard of drugs like methadone and buprenorphine, naloxone. A very close relative of naloxone is called Naltrexone. These drugs are used to treat opioid use disorder. They’re effective in some patients. Yet in the one hour that we’re going to chat five people are going to die from an opioid overdose. We have something that we think can be a life changer. This drug can protect people from their own bad behavior. It can protect them from the adverse and toxic effects of opioids.

Let’s just say they do the drug, and they get the MCAM. They want to do the drug again for some unknown strange reason, but that drug, the bad one, it’s not going to work on them, right? 

Dr. France: That’s exactly right. The high that they’re seeking – they’re not going to feel when MCAM has been given because that drug can no longer bind to those places in the brain. MCAM is occupying them and it will occupy them for quite some time.

So what’s the history of MCAM? How did that come to pass? How long has it been around? 

Dr. France: MCAM is chemically a very close cousin to a drug called buprenorphine which has been around for many, many years. Buprenorphine was discovered by John Lewis and Colman Reckitt in the UK. Their goal was to find a better morphine and they found a better morphine in some ways, because buprenorphine has some activity that makes it better in the marketplace as a pain reliever. Buprenorphine has also become the frontline medication for treating people who suffer from opioid use disorder because if they take buprenorphine they don’t feel the urge to take heroin, fentanyl or other sorts of illicit opioids. The same man, John Lewis, after he had discovered buprenorphine decided he wanted to make a better buprenorphine and he made a batch of drugs. One of those drugs is Methocinnamox or MCAM. This was discovered and first published upon in 2000 and sort of discarded as a novel drug but one that may not have any more applicability other than as a research tool. It came to our attention a few years ago when the National Institutes of Health were seeking assistance from investigators to think of new ways to try to address the opioid crisis. We revisited data that had been generated by my colleague Dr. Woods at the University of Michigan with MCAM and decided to test proof of principle to see if it might be useful both for treating opioid use disorder and for reversing opioid withdrawal. It turns out it has very exciting properties on both of those venues in terms of rescuing and protecting people. So it’s a compound that was discovered nearly 20 years ago but really had not been studied nearly at all until the last few years. We are now working 24/7 trying to develop it.

So tell us the mustard story and also the fact that it’s been around 19 years but suddenly somebody says, oh, it sort of goes away and they come back and they say, hey, you guys out there in the field, what do you think? 

Dr. France: The mustard story is that Coleman’s mustard has been made in the UK for many, many years and Coleman joined ranks with a company called Reckitt that made household cleaning products back in the 1930s. So Coleman knew a lot about food chemistry and Reckitt knew a lot about chemical structures of cleaning solvents. They put them together and hired a couple of very clever scientists – John Lewis the man I mentioned who is the chemist – to discover this new morphine. So had they not had Coleman mustard to be able to fund this project with Reckitt to discover the new morphine, we likely would not be here today because it went from mustard to buprenorphine to methocinnamox. You’re exactly right about the course of medicine and the course of science. We often don’t know where we’re going. It’s as though we have blinders on. We sort of reach around and find things that are interesting. MCAM has been lying on the shelf for 20 years and we didn’t have a conceptualization of how useful it might be until relatively recently. We have now discovered the potential utility of it and I think it’s going to be very dramatic.

How did that big huge need enter our world? Why at that point in time did fentanyl and these opioids become so dangerous? 

Dr. France: Well there’s a lot of questions embedded in what you just said. I think there is plenty of guilt to go around and we’re seeing it every day in the newspapers and it started certainly more than four years ago. Those of us who’ve been in the opioid field knew that there was a crisis emerging 15 to 18 years ago with the overprescription of opioids and opioids being put on the market in a manner that was not aligned well with the science – notions like giving drugs that have a very long duration of action will be very safe because individuals won’t feel the need to take them multiple times through the day. Well that may be true that they won’t feel the need to take them multiple times through the day, but with that very long duration of action you increase the likelihood of a physical dependence developing. So when people try to discontinue the drug they can’t because they’re physically dependent and the withdrawal is so adverse that they feel the need to take the drug. So that sort of miscommunication about the properties of drugs that may or may not be safe lead clearly to the overprescription of opioids. The medical community has plenty of blame to go around for the misuse of those drugs, overprescribing and prescribing them for indications that were inappropriate. That created a huge marketplace in the United States for people who had a significant appetite for opioids and individuals with bad intentions saw that market and exploited it – many of them from Mexico because they had very cheap easily-available widely-marketed heroin and it was very potent. So individuals who would never imagine taking an illicit opioid much less putting a needle in their arm had developed a physical dependence largely because of prescription opioids and prescription opioids became exceptionally expensive. In New York several years ago an Oxycontin pill, famous OxyContin, may cost 50, 60 or $70. A bag of heroin will cost $15 for the same high. Do the economics. These people marketed these drugs in absolutely a malicious manner and took over the marketplace from individuals – many of whom had developed their habits with prescription opioids and now, perhaps reluctantly but eventually if no other reason for economic reasons, switch their habit to heroin. The heroin was sufficient for them. It maintained the high that they had become accustomed to or in some cases the pain relief that they had sought from the prescription opioids. Then came along other marketers who realized that while heroin is a fine drug, there are even more powerful drugs out there like fentanyl and related counterparts. Now fentanyl was discovered many years ago. It’s a fantastically useful drug in medicine but it’s a very potent, very powerful opioid and likely to be abused. The unfortunate aspect about – one of the unfortunate aspects about fentanyl is that its chemistry is very simple. Someone with a very rudimentary knowledge of chemistry can make analogs of fentanyl and in fact make drugs that are much more potent and much more dangerous than fentanyl. So then that marketplace took over largely from clandestine labs overseas, many of them in China. These drugs were shipped through places like Canada and brought into the United States through a porous border and their potency is so phenomenal that even a very small package of it will make huge amounts of money in the marketplace. So the transition then went from prescription opioids to the second phase which was heroin to now the third phase we’re in which are the fentanyl derivatives. The fentanyl derivatives are used widely not just by people who think they’re taking heroin or think they’re taking Vicodin but people who think they’re taking something else. These people have very bad intent and they adulterate many different kinds of drugs with fentanyl. In fact people who think that they’re abusing cocaine in some situations will get cocaine that has been laced with fentanyl and much to their surprise their respiration goes down and they may die. So it’s a very complicated problem. Where we are today it’s hard to say what the primary factors were but clearly overconsumption of opioids. We in the United States take far more opioids than the rest of the world. We consume a huge fraction of opioids despite the fact that I suspect our pain need is not really greater than anybody who lives in a place like Ireland or France or anywhere else.

So, how much of a game changer MCAM?

Dr. France: We think it can be a game changer in several venues because of this unusual property that it lasts a long time and its effects cannot be overcome by taking more drugs. So on the one hand people can be rescued from opioid overdose and they don’t have to be managed medically for up to a week or longer because they will be protected from any further overdose. Another situation in which we think MCAM can be a game changer is to treat opioid use disorder. So these are people who have had an opioid use problem, have stopped taking opioids, but are concerned about the possibility of relapse. If treated with MCAM – particularly MCAM if we can formulate it in ways that it extends its duration even beyond seven days – and we’re working aggressively on that – to perhaps provide protection over many weeks and perhaps months, then those individuals if they feel the urge to relapse they’re not going to get any high from the drug that they take. That should help extinguish their behavior. I should say we don’t believe that there are any magic bullets in this field. It’s a lifestyle change. It’s a behavioral change and it can come with the facilitation of drugs but it has to come with other changes in lifestyle. The other thing is to protect individuals who may go into harm’s way. We talked earlier about law enforcement and military personnel. In fact those two sectors are very interested in MCAM because of the kinds of dangerous situations that law enforcement and military personnel can find themselves in with regard to the weaponization of opioids.

How prevalent is MCAM now say in an E.R. or with the military, is it widespread? 

Dr. France: MCAM is not available for use in humans. Remember we just pulled this off the shelf a couple of years ago. We are working very aggressively and we have been supported very nicely by the NIH. Our hope – honestly our optimistic hope is to have this into Phase 1 clinical trials in humans within 24 months perhaps as little as 18 months. We have done a lot of work on it here in San Antonio and we think with the assistance of the FDA and the NIH that we can get this into people soon because there’s a desperate need for this drug.


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