The Problem with Vivitrol®

(https://www.vivitrol.com/opioid-dependence/what-is-vivitrol)

Fascinating post by guest contributor Amy Dunn, graduate student at the Rockefeller University!


What is Vivitrol®? This question is posed in countless ads depicting attractive young people across target states, such as MA, NY, NJ and PA. The ads do little to answer the question – instead just giving a drug name and a website. Vivitrol®, made by the Boston-based company Alkermes, is the brand name for the drug naltrexone and is used to treat both alcohol and opiate addiction.

Opiates like heroin or oxycodone work by stimulating the mu opioid receptor in the brain. This leads to the euphoric and rewarding effects that are characteristic of these drugs. The two most popular medications for treating opiate addictions, methadone and buprenorphine, both work by stimulating that same receptor in a slightly different way. This relieves the cravings, but doesn’t cause the same “high” as heroin or oxycodone. Methadone and buprenorphine are known as agonist, or replacement, medications. Dr. Simon Says Science wrote an excellent article for Addiction Blog that compares methadone and buprenorphine and explains how they work in greater detail. Naltrexone, on the other hand, is an antagonist of that same receptor – meaning that it completely blocks the effects of any opioid. While it seems counterintuitive, medications that stimulate the mu opioid receptor and medications that block the mu opioid receptor have both been proven to be effective treatments for opiate addiction.

Naltrexone was approved by the FDA in the 1980’s and was originally formulated as a daily pill, however it was difficult to get people to adhere to taking their medication. Because naltrexone is a mu opioid receptor antagonist, it can lead to unpleasant feelings that are the opposite of the euphoria felt with an opiate agonist. People with addictions could stop taking the medication if they wanted to get high instead. Because of these adherence issues, the drug bounced around between companies. In addition to these issues with compliance, it was difficult for companies to market an addiction medication because of the social stigma. Addiction is often seen as a moral problem instead of a medical one, which makes selling medications for addictions very difficult.

Naltrexone became far more practical when it was reformulated as an extended-release injection. The extended-release injection lasts for a month, greatly reducing the problem of adherence. Vivitrol®, the brand name for the extended-release naltrexone introduced by Alkermes, was first approved in 2006 for the treatment of alcohol addiction. Following a successful clinical trial in Russia, it was also approved for treatment of opiate addiction in 2010. Despite poor initial sales, the popularity of Vivitrol® has grown rapidly in the past couple years.

Vivitrol® Sales: (https://www.scribd.com/document/351102245/Alkermes-2016-Analyst-and-Investor-Event-Presentation#from_embed)

 

Vivitrol® is still far less utilized than methadone and buprenorphine, but this is expected probably because it is much newer on the market. Importantly, not everyone responds well to methadone or buprenorphine, and having another option for the treatment of opiate addiction should be a good thing for everyone. However, a disturbing pattern has emerged in the past couple years regarding the ethics of Alkermes’ marketing strategies and scientific data. They are missing key scientific data, and actively engaging in strategies to undermine the use of agonist medications that compete with Vivitrol®. While these marketing strategies may or may not be illegal, they still raise important questions about the ethical obligations of pharmaceutical companies to their patients.

The Science on Vivitrol®

In order for the FDA to approve a drug, a drug company must first prove that the drug is effective through a clinical trial. Clinical trials are very tightly regulated in the US which makes sense because you’re testing a drug that is technically still experimental and could be dangerous to people. Not only do you need to prove that your drug is safe, but you also need to prove that it is at least as effective as other drugs out there that treat the same condition. This is where there are holes in the data on Vivitrol®.

The clinical trial that convinced the FDA to approve Vivitrol® was done in Russia.3 Clinical trials are done in other countries for many reasons. Companies may be trying to skirt the tight regulations here in the US, or they might just need to work with a patient population that is found more commonly in other places. The FDA reviews the study design and the data to see if they want to approve the drug regardless of where the study was done. The clinical trial on Vivitrol® was designed to see if Vivitrol® was effective for treating opiate addiction, but did not compare it to either of the other approved medications for opiate addiction (methadone or buprenorphine). Neither of these agonist treatments is available in Russia. In fact, both are illegal because they are opiate agonists. Alkermes only needed to prove that Vivitrol® was more effective than placebo in this case. The results were promising – almost 90% of the addicted persons who received the naltrexone shot remained abstinent during the test period, compared to just over 60% of the control group. This was enough evidence to get FDA approval, however to date there are no clinical trials comparing Vivitrol® to either methadone or buprenorphine. In addition, there was no follow-up study examining the long-term outcomes of the participants of the clinical trial in Russia.

Since it has been approved, there have been several other clinical trials examining the efficacy of Vivitrol® in different populations (although none of these studies compared it to buprenorphine or methadone). There are still concerns about adherence to Vivitro®, as well as the possibility that a person could take a dangerous amount of opioids in order to overcome the blockade effect. Because it’s an antagonist, if an addicted person takes naltrexone while they still have opiates in their system, the naltrexone will both stop the euphoric effects of the opiate and also cause withdrawal symptoms. In fact, a person has to be over a week opiate-free and have already gone through withdrawal before they can begin naltrexone treatment.

However, no medication is ever perfect. While there are still unanswered questions about Vivitrol®, it is clearly an addition to the toolbox that healthcare providers can use to help people fight addictions. It is important that these scientific concerns are discussed and addressed, and that these issues are clearly presented to the public so that people can make informed decisions about their medications.

The Marketing on Vivitrol®

(www.vivitrol.com)

To understand more about how Alkermes is advertising Vivitrol®, we can look at a screenshot of their main website listed on their advertisements (www.Vivitrol.com). This language – “the first and only once-monthly, non-addictive medication” is problematic.  While they are correct in characterizing naltrexone as “non-addictive”, this wording implies that the other medications that are available (methadone and buprenorphine) somehow are addictive. This same language is often used in a 2016 investor presentation as well, where they describe agonist therapy as “maintain[ing] physiologic dependence on opioids”. This is scientifically correct; a person who is using agonist medication may indeed be dependent on their medication. This simply means that they would experience negative physiological consequences if they abruptly stopped use. It does not mean that they are addicted. “Addiction” is a physiologic dependence combined with compulsive drug-taking despite negative consequences. Alkermes is conflating these two terms in a way that is confusing, and is meant to manipulate the consumer into equating agonist therapies with addicting opiates of abuse. While their statement that agonist therapies lead to dependence is not incorrect, it is still reinforcing a very damaging stereotype that agonist therapy is just “replacing one drug with another.” This stigma against agonist therapies is a major hurdle for the treatment of opiate addictions. Alkermes actively reinforces and uses this stereotype in order to promote Vivitrol® as the “only non-opioid treatment.”

(https://www.scribd.com/document/351102245/Alkermes-2016-Analyst-and-Investor-Event-Presentation#from_embed)

In addition to portraying Vivitrol® as a better and safer alternative to agonist therapies in the public sphere, Alkermes is also deliberately promoting this view in the political realm. This is noted in the slide from an investor presentation that outlines their marketing strategies, above.  NPR and Side Effects Media published an excellent article detailing their investigation into Alkermes’ political involvement.  They describe Alkermes lobbyists presenting to government committees on addiction therapy and promoting the idea that agonist therapies are “replacing one drug with another”. There is overwhelming scientific evidence supporting methadone and buprenorphine as effective treatments for keeping people with addictions off of heroin and able to live their lives without experience frequent drug cravings. Despite this, there are many decision-makers in the government who do not want to support their use in treatment. Republican Rep. Tim Murphy described agonist therapy as “government –supported addiction” at a meeting in March 2015. He has received political donations from Alkermes. Tom Price, the new Health and Human Services Secretary, received a great deal of criticism for his statement that agonist therapy was “substituting one opioid for another” – despite the department’s website explicitly stating that it supports these kinds of evidence-based treatments.

Alkermes’ strategy of reinforcing of this stereotype leads to real policy consequences. The NPR and Side Effects Public Media report describes several bills that contain language steeped in these stereotypes – specifically instructing treatment providers to strive for “the goal of opioid abstinence.” This is beneficial for Alkermes, as Vivitrol® is the only non-opioid treatment available. The science however, does not indicate that opioid abstinence leads to better outcomes for patients than maintaining their agonist therapies. The report includes drafts of several bills that even mentioned Vivitrol® by name, although it was later removed because of ethical concerns. Alkermes lobbyists have also supported tightening regulations for methadone and buprenorphine, which is incredibly problematic given how restrictive the regulations already are for treatment providers.

Alkermes may not be making explicitly false claims in its marketing, but it is certainly playing off of existing harmful biases in order to further their sales. Whether or not this is illegal is debatable; it is illegal under the Federal Trade Commission for companies to “mislead” consumers. At the very least, it is incredibly unethical for a company to be so actively promoting stereotypes and policies that harm the very patients that they claim to be helping. This falls under the larger umbrella of the issues of advertising, pricing and political involvement of the pharmaceutical industry in our country. While there are no easy fixes, it is important that companies like Alkermes are held responsible for their unethical behavior and that consumers are able to make informed decisions about their treatment based on the available research.


About the Author: Hello! I’m currently finishing my 3rd year of graduate school at Rockefeller University. I’m studying the cell signaling changes caused by drugs of abuse and investigating the ways we can use those different pathways to treat addictions. In addition to learning more about the science of addiction through my research, I’m also interested in learning about the different political and social issues surrounding drug addiction. All of the views and opinions here are entirely my own and definitely don’t reflect those of my lab or institution! My email address is adunn@rockefeller.edu.

Response to the June 2017 New Yorker Article on the Opioid Epidemic

At this point, I would think that knowledge about the vastness and seriousness of the prescription opioid and heroin epidemic, the biggest threat to American health and well being since the HIV/AIDS epidemic, would be common knowledge. Of course, given the abundance of shiny Internet things to tantalize easily distracted Americans, this is unfortunately not necessarily the case. Thankfully the New Yorker, with their characteristic excellence in reporting, has just released a superb and humanizing article on the opioid epidemic in their June 5 & 12, 2017 issue.

Read the article here.

The piece puts a much-needed human face to the horrors and misery of opioid addiction and the too-frequent death by overdose. Margaret Talbot, the article’s author, zeroes in on Berkeley County, West Virginia, in the heart of a region of the country hardest hit by the epidemic. I don’t want to give away much (because you should actually just read the article) except that the stories are heart wrenching yet balanced, and thorough in way that only the New Yorker can deliver. While the article is largely about the lives of people affected by and fighting against the epidemic, I was disappointed with a couple of points that were either made incorrectly, weakly, or not at all.

First, the article barely talks about how the epidemic arose in the first place. It mentions Purdue pharmaceuticals, the bastards behind Oxycontin (drug name: oxycodone), and that prescription opioid abuse led to heroin addiction but does not describe how the surge in addiction to prescription opioids occurred in the first place. The article describes the main problem with Oxycontin is that it can be crushed and snorted but a 2010 formulation of the drug reduced this risk. While this is indeed true, the article neglects to mention that when someone is first prescribed an opioid like Oxycontin for chronic pain (as was the case in the late 90s and early 2000s despite any evidence for the effectiveness of opioids in the treatment of chronic pain), the addictive potential of opioids often led to opioid substance abuse disorder in people who took it as prescribed (see this comprehensive article for more info). This is the big point, many of the people that eventually abused opioids started down that road by taking the drug as prescribed! Talbot incorrectly frames the big picture problem but she then goes on to correctly describe how those addicted to prescription opioids found their way to the cheaper and more abundant heroin.

The article goes on to mention the CDC’s release of guidelines on opioid prescription but fails to cite that this guidance came out as late as March, 2016, well after the epidemic had already taken root and thousands were already addicted and dying of overdose (I wrote an article on the CDC’s guidelines last year and highly recommend you read that article too if you want to learn more). The CDC’s guidance is mainly about the point I made above, that the over-prescription of opioids is the real cause of the epidemic, not just the crushable version of Oxycontin, and the limitation of opioid prescription is one of the huge policy interventions that is needed.

Later in the article, Talbot introduces us to Dr. John Aldis, a retired U.S. Navy Physician and resident of Berkeley County, WV who took it upon himself to educate people on how to use Narcan (generic drug name: naloxone), the treatment for opioid overdose. Dr. Aldis makes the critical point about the importance of medication-assisted treatments such as Suboxone (generic drug name: buprenorphine) and methadone. I appreciated the point made in the article that some patients may need these vital treatments long-term, or even for life, to combat the all-consuming single-mindedness of opioid addiction. However, beyond this passing mention, I felt that medication-assisted treatment was only weakly covered. There is still a great deal of ignorance about these treatments. Indeed, current HHS secretary Tom Price falsely characterized them as “replacing one opioid with another” and was majorly criticized by addiction experts. The reality is that there is overwhelming scientific evidence (I’ve written plenty on this site) describing the effectiveness of methadone and buprenorphine at 1) keeping addicts off of heroin, 2) allowing them to be able to live their lives without suffering from withdrawals and cravings, and 3) most importantly, keeping them alive. Talbot could have done a much better job of really hammering these points home but she seemed reticent, for some reason, to discuss it in detail in this article.

Finally, the article repeatedly emphasizes the importance of rehab clinics and tells the story of a huge victory for Martinsburg, WV (a town in Berkeley County) when the city council agrees to open a clinic in the town itself. I do not want to discount the importance of an addict assessing their addiction and taking an active role to end it, but this article does miss another critical point: rehab clinics only exist because addiction medicine is not part of medical school curricula and most hospitals are ill-equipped to treat those suffering from addiction. I feel this article could have really made the case for the importance of training for doctors in addiction medicine and the necessary shift that needs to happen for addiction treatment, a move away from overpriced (and often ineffective) private rehab facilities, and to public hospitals. Unfortunately, this point was not made.

Despite these missed opportunities, I commend Talbot and the New Yorker for a well-written article and thank them for this important piece that I encourage all to read.

 

Methadone Maintenance Therapy Works-End of Story

helping hands (pixbay.com)

I hate to be condescending but how the scientific community perceives a phenomena and how the public at large perceive the exact same thing can be starkly different.

For example, there is still a debate over the scientific legitimacy of global warming and climate change. Of course, this flies in the face of reality. In the scientific community, there is no more doubt over climate change than there is over heliocentricity (the theory that states the Earth revolves around the Sun). Study after study comes to the came conclusion, the scientific evidence is overwhelmingly in favor. But I’m not writing to debate climate change.

The same type of dichotomy exists for replacement/maintenance therapies for addiction. Methadone and the related compound buprenorphine (Suboxone, one of its formulations) are still considered controversial or ineffective or “replacing one drug for another.”

(wikipedia.com)
Methadone pills. (wikipedia.com)

In brief, methadone is a compound that acts on the same target as heroin (the mu opioid receptor) but unlike heroin, it acts for a very long time (24hrs). Dr. Vincent Dole, a doctor at the Rockefeller University in New York, and his colleague, Dr. Marie Nyswander, had the brilliant idea of using this very long-acting opioid compound as a way of treating heroin addiction. Indeed, methadone has the advantage of not producing the intense, pleasurable high that heroin produces but is still effective at curbing cravings for heroin and eliminating withdrawal symptoms. Dole and Nyswander published their first study in 1967 and methadone has been an approved—and effective—treatment for heroin addiction worldwide ever since.

However, controversy over the use of methadone exists. Even the opening of a methadone clinic can incite protests. The persistence of negative attitudes towards methadone and the stigma against treating addiction as a medical disease has prevented addicts from receiving proven medical treatments that are effective at curbing cravings and actually keeping them off of heroin and in treatment programs.

So just for a moment, let’s suspend our preconceived notions about what methadone is or how it works and let’s just ask our selves two simple questions:

 Does methadone work?

Does methadone keep addicts off of heroin and in treatment?

The answer is a resounding YES!

 

Mattick JP et al. Methaodone. 2009 title

Many controlled, clinical studies have examined the effectiveness of methadone. But a comprehensive comparison of methadone versus control, non-medication based treatments has not been considered amongst the various studies.

Researchers at the Cochrane Library performed this type of comprehensive analysis. Data was considered from 14 unique, previous clinical studies conducted over the past 40 years. Researchers compared methadone treatment versus control, non-medication based treatment approaches (placebo medication, withdrawal or detoxification, drug-free rehabilitation clinics, no treatment, or waitlist).

11 studies and 1,969 subjects were included in their final analysis.

 Read the full paper, published in 2009, here.

The results were clear. Methadone was found to keep people off of heroin and in treatment more effectively than control treatments. Urine analysis confirmed methadone-treated addicts were more likely to be heroin-free and regularly seeking treatment.

Of course, as I stated above, this is nothing new. But it’s important to note that abstinence therapies or treatments that encourage addicts to go “cold turkey” don’t really work; inevitably, relapse will occur. A medical treatment exists to help addicts fight their cravings so their brains are not fixated on obtaining heroin and these people are able to regain normal daily functions. And in time, methadone doses can be tapered down as intensity and frequency of cravings decrease.

The debate now should not be on whether methadone works, but on how to use it effectively and how to expand its use so that as many people as possible can benefit from it.

Most importantly, methadone helps an addict to return to normal life. End of story.