04/2/24

Is Indivior a Good Steward of Its Opioid Treatments?

Image by Лечение Наркомании from Pixabay

Fierce Pharma reported in 2020 that the former Indivior CEO was sentenced to six months in federal prison for his role in misleading officials about the supposed dangers of Suboxone tablets. He was also fined $100,000 and forfeited another $500,000. But it seems now he’d like to be a consultant to individuals or companies attempting to bring a new drug to market. However, the FDA rejected that plan for now. On February 27, 2023 he was debarred by the FDA for “5 years from providing services in any capacity to a person that has an approved or pending drug product application.” What was he involved in that resulted in his prison sentence and debarment by the FDA?

According to Fierce Pharma, on October 23^rd, 2023, Indivior agreed to pay $385 million to settle lawsuits in the U.S. brought by drug wholesalers claiming it illegally suppressed generic competition for Suboxone. But that’s not all. The company also agreed in June of 2023 to pay $102.5 million to settle a 2016 lawsuit charging that Indivior’s actions when switching from a tablet to an oral film form version of Suboxone was done to extend its monopoly with Suboxone. AND in August of 2023, it offered $30 million to settle with health plans making similar claims. This was in addition to the $300 million Indivior paid in 2021 to resolve claims it “falsely and aggressively” marketed the drug, which led to the misuse of state Medicaid funds.

All this happened after Indivior was sued in 2020 by its former parent company, Reckitt Benckiser, seeking $1.34 billion in damages tied to its marketing scheme for Suboxone film. Then on December 20, 2023 Indivior announced that it had entered into a settlement agreement with Actavis Laboratories, a subsidiary of Teva Pharmaceuticals, to resolve patent disputes regarding Actavis’s Abbreviated New Drug Application (ANDA) for generic buprenorphine and naloxone sublingual film. Under the settlement, Actavis can launch the generic film products in ANDA no earlier than January 31, 2025.

It seems Indivior as a company is trying to leave its chaotic and costly past behind. In About Us, Indivior said it “is a global pharmaceutical company working to help change patients’ lives by pioneering life-transforming treatment for addiction and other serious mental illnesses.” Their vision is to provide access to evidence-based treatment to the millions of people across the globe who suffer from substance use and serious mental illness. They also say they take their role as a steward of their medications extremely seriously:

We cultivate a culture of integrity and commit ourselves to the highest standards of governance. We believe our long-term success is directly linked to operating in a responsible way and in a way that minimizes our impact on the environment. We support efforts to educate around safety and proper use of our medication-assisted treatments.

Origins of Indivior

In case you’re not familiar with the company, here is a brief history of Indivior from Wikipedia and “The Opioid Buzzard.” It was established as the buprenorphine division of Reckitt Benckiser in 1994. Suboxone and Subutex were approved for the treatment of opioid addiction in October of 2002. They were both sublingual (under the tongue) tablets. Suboxone consists of buprenorphine and naloxone; Subutex was just buprenorphine. They came to market in 2003.

In 2007 Reckitt Benkiser (RB) acquired the rights for the sublingual film version of Suboxone from MonoSol Rx. RB knew its patent exclusivity for Suboxone and Subutex would expire in 2009, so they submitted a New Drug Application for the film version of Suboxone, which was approved in August of 2010. In their 2011 annual report (no longer retrievable from its website), RB indicated to their shareholders that competition from generics could take up to 80% of the revenue and profit from the U.S. Suboxone market. But they expected “that the Suboxone film will help to mitigate the impact.”

In September of 2012 RB announced that they were voluntarily withdrawing Suboxone tablets from the market because of data they had received from the U.S. Poison Control Centers suggesting there were higher rates of pediatric overdose on the tablet formulation than the film version. They said they would take the tablet form off the market to “protect public health and safety.” The very same day RB filed a “Citizen’s Petition” with the FDA calling for the agency to postpone the approval of generic version of Suboxone in the interests of public safety. Subutex tablets were discontinued in 2011 and Suboxone tablets met the same fate in in 2012. For more on this action by RB, see “The Opioid Buzzard.”

In December 2014 Reckitt Benckiser made the buprenorphine division a separate company named Indivior. By February 2015, it was capitalized on the London Stock Exchange at $3.1 billion. And on April 9^th 2019, a federal grand jury indicted Indivior for allegedly engaging in an illicit national scheme to promote Suboxone. See “The Pied Pipers of Suboxone” for more on this topic.

Indivior Products for Opioid Use Disorder

The Indivior products currently available in the U.S. to treat opioid use disorder include: Suboxone, a buprenorphine and naloxone sublingual film, Opvee, a nalmefene nasal spray for the emergency treatment of known or suspected overdose of opioids, and Sublocade, an extended-release injection of buprenorphine. Opvee and Sublocade are newer products than Soboxone and will be described below.

NPR noted Opvee was developed by Opiant Pharmaceuticals, which was acquired by Indivior in March of 2023. Opvee was approved by the FDA in May of 2023 and is similar to Narcan which contains naloxone. It apparently has a longer-acting effect than naloxone, which has some experts concerned. Nevertheless, Nora Volkow, the director of the National Institute on Drug Abuse, said: “The whole aim of this was to have a medication that would last longer but also reach into the brain very rapidly.”

An adverse side effect of opioid reversal drugs like Narcan and Opvee is they create intense withdrawal symptoms including: nausea, diarrhea, muscle cramps, anxiety, restlessness or irritability, increased blood pressure, rapid heart rate, body aches, and others. Important Safety Information for Opvee cautioned that the use of Opvee (leading to abrupt postoperative reversal of opioid depression) “may result in adverse cardiovascular effects” in people with preexisting CV disorders. So, these patients should be closely monitored in a healthcare setting. And it warns that some patients may become aggressive when an opioid overdose is reversed (treated) with Opvee.

With naloxone (Narcan), these symptoms could last 30 or 40 minutes. With Opvee (nalmefene) they can last six hours or more, “requiring extra treatment and management by health professionals.” GoodRx Health said: Opvee’s half-life is about 11 hours, while Narcan’s half-life is about 2 hours. Read between the lines here. A person uses opioids to experience the high or euphoria AND to avoid withdrawal. So Opvee immediately blocks the high and brings on withdrawal. It extends the withdrawal symptoms to six hours or more, with the potential of the treated person wanting nothing less than to find more opioids to cope with the withdrawal and driving them to use a higher dose of opioids to overcome the nalmefene—with the potential of adverse cardiovascular effects in people with preexisting CV disorders.

If this “treatment” occurs, as is likely, outside of a healthcare facility, the person or persons who administered the Opvee will have to convince person to go to an emergency department or other healthcare facility. There is a better chance of success if the withdrawal symptoms only last 30 or 40 minutes than six hours or more. No wonder some individuals get aggressive when treated with Opvee. Should it be limited to use with overdose victims who are already in a healthcare facility or by emergency responders like EMT or police?

Dr. Lewis Nelson of Rutgers University, a former advisor to the FDA, said the risk of long-lasting withdrawal is something they try to avoid. He added a second or third dose of naloxone is easy enough to give and works perfectly well.

Indivior said it is still considering what to charge for its drug. It will compete in the same market as naloxone, where most buyers are local governments and community groups that distribute to first responders and those at risk of overdose. Indivior has told investors that Opvee could eventually generate annual sales between $150 million to $250 million.

Sublocade was approved by the FDA in November of 2017. It is a monthly injection of buprenorphine to treat individuals with moderate to severe opioid use disorder. “It is indicated for patients that have been on a stable dose of buprenorphine treatment for a minimum of seven days.” It is a drug-device combination product that is injected under the skin (subcutaneously) as a solution, but forms a solid deposit or depot of buprenorphine. After the initial formation of the depot, buprenorphine is released as the depot biodegrades.

The monthly injection of buprenorphine in Sublocade is another treatment option for opioid use disorder (OUD). It has the advantage of gradually releasing buprenorphine at a controlled rate, meaning that the levels of buprenorphine stay consistent in the blood throughout the month. In a study reported on in the above-linked description on how Sublocade works, Indivior provided a chart illustrating how buprenorphine levels were delivered at sustained levels, after a required preliminary period of daily oral buprenorphine for at least 7 days to control withdrawal symptoms. The required daily use of oral buprenorphine helps assure the healthcare provider the person did in fact stop their use of opioids before they began their daily use of Suboxone because buprenorphine acts as a partial antagonist, blocking the ability of many opioids to cause an effect.

Should the person decide to stop taking Sublocade, the terminal half-life of Sublocade is 43 to 60 days. According to Drugs.com, it usually takes four to five half-lives for a drug to be totally eliminated from the body. So, no trace of buprenorphine from Sublocade should be found after 172 to 300 days. This raises the potential use of Sublocade as a tool for slow tapering once the individual has reached a steady-state (4-6 months), instead of treatment with Sublocade continuing indefinitely.

A Slow Buprenorphine Taper with Sublocade?

Dr. Leeds, a Suboxone doctor in Fort Lauderdale FL, described just such a way Sublocade could be used to taper off Suboxone. He said many patients often want to know from their first visit to a Suboxone doctor if there is a way to eventually get off Suboxone. Their reason is the buprenorphine in Suboxone is an opioid drug and causes physical dependence like all opioids. If a patient taking Suboxone quits treatment early, they will develop withdrawal symptoms. A gradual taper is the solution to minimize the physical opioid withdrawal symptoms.

However, the medication is not well-designed for a taper. Doctors who help their patients with tapering off Suboxone quickly realize that the Suboxone sublingual films are not available in enough dosage increments to all for proper gradual tapering.

In order to avoid serious withdrawal symptoms, a patient most often must reduce their dosage gradually, to the lowest dose possible, such as buprenorphine 0.25mg daily, or even less. Unfortunately, the lowest Suboxone dose is 2mg.

Additionally, the manufacturer, in the Suboxone prescribing information, states that patients should not cut or split the tablets or films. Suboxone makers are clearly not interested in helping patients with tapering off Suboxone.

Dr. Leeds noted that since the subcutaneous buprenorphine shot takes many months to fully wear off, “it does seem possible that it might help some patients with the tapering process.” However, the buprenorphine taper would be off-label and experimental at this point. There would be no available guidance from experts, “because Sublocade has not been widely used for Suboxone tapering.”

For the present, he does not recommend finding a doctor willing to use Sublocade to taper off Suboxone. But he encouraged interested people to reach out to researchers and research centers in the field of opioid use disorder treatment. “If Suboxone scientists are aware that people are interested in this research, they might decide to seek funding for such studies.” He also suggested there may be doctors who are using Sublocade off-label for Suboxone tapering, who may have anecdotal information to help other interested doctors.

Drugmakers are quick to recommend that doctors get their patients onto their medications. Yet, they do little to guide doctors in getting patients off of these meds when treatment has been completed.

Are you listening, Indivior? You describe yourself as “a global pharmaceutical company working to change patients’ lives by pioneering life-transforming treatment for addiction.” You further said you believed your “long-term success was directly linked to operating in a responsible way.” Is it responsible to neglect to provide guidance for individuals who would like to taper off their use of Suboxone and Sublocade, which are opioids—meaning they make their users physically dependent on them. Does the safe and proper use of your medication-assisted treatments require you to ignore those who want a safe and proper method of tapering off of them?

If you truly take the stewardship of your medications extremely seriously, shouldn’t you be willing to fund research into Suboxone tapering with Sublocade?

01/11/22

The Cost of Buprenorphine-Assisted Recovery

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As I was leaving a rescue mission in Pittsburgh, I saw a homeless man curled up in a fetal position in front of the building. He was unresponsive when I called out to him, so I went back inside and told someone to call 911. While I was doing this, another staff member got Narcan and administered it to the man. When the paramedics arrived, they were eventually able to convince him to go to the emergency department of a local hospital. But he refused further treatment services there and was released.

This is a typical response of those who experience a nonfatal opioid overdose. According to Davis et al in an article published in the Annals of Emergency Medicine, opioid users resist treatment with buprenorphine even though it significantly reduces overdose mortality. In an attempt to minimize this treatment void, some EMS paramedic units are administering buprenorphine to patients almost immediately after reviving them from an opioid overdose. STAT reported back in June of 2019 that New Jersey’s health commissioner authorized paramedics to offer the drug to patients after their overdose has been reversed with naloxone.

The first-in-the-nation model has a twofold purpose, health officials said: Beyond treating the withdrawal symptoms that can result from a naloxone revival, administering buprenorphine on scene could serve as an immediate transition to longer-term treatment.

Dr. Dan Ciccarone, a professor who studies heroin use and the opioid epidemic, said while the prehospital use of buprenorphine comes out of left field, “It’s a potentially brilliant idea.” He sees this as an attempt to treat the person in as well-meaning and patient-centric way as possible. “And that means naloxone plus a softer landing with buprenorphine.” Doctors in numerous emergency departments already prescribe buprenorphine in an effort to provide relief after reversing an overdose. Extending that ability to paramedics “is a new frontier.”

As a safeguard, New Jersey’s 1,900 paramedics will need to obtain permission from the emergency physician overseeing their unit before administering buprenorphine when responding to an overdose call. The supervising physician must have a DEA waiver [and undergo training] to prescribe buprenorphine, a spokeswoman said.

We need to think beyond how we’ve traditionally treated nonfatal opioid overdoses. A CDC press release indicated in the 12-months ending in April 2021, the estimated overdose deaths from opioids increased from 56,064 in April of 2020 to 75,673. Overall drug overdoses increased 28.5% during the same period of time. An interactive web dashboard is available and can gives you predicted overdose data for individual states. The overall increase in overdoses for the United States is 28.5%.

Pennsylvania was among the states hardest hit by the opioid epidemic. In 2018, it had one of the highest death rates from drug over doses, with 65% of 2,866 fatalities involving opioids. Policy responses made to mitigate the spread of COVID-19 in Pennsylvania made the problem worse. Analysis of data from the Pennsylvania Overdose Information Network for both fatal and nonfatal overdoses revealed statistically significant increases across some of the populations most affected by opioids before the pandemic.

In “Assessing the Relationships Between COVID-19 Stay-at-Home Orders and Opioid Overdoses,” the authors said the stay-at-home order in Pennsylvania contributed to a statistically significant increase in opioid overdoses compared with preceding months. See “Unintended Consequences of COVID-19” for more on this topic. It seems this increase in opioid overdoses may have partly motivated Pittsburgh to become only the third city in the country to announce a pilot group of Emergency Medical Services (EMS) paramedics that will administer prehospital buprenorphine.

On November 22, 2021, The Office of Community Health and Safety in Pittsburgh announced paramedics had completed training to administer prehospital buprenorphine and began implementing the practice over the weekend before Thanksgiving. In September, the Pennsylvania Department of Health Bureau of EMS approved the Prehospital Buprenorphine Pilot Program for the City of Pittsburgh’s EMS. The pilot program was designed by the Bureau of EMS in partnership with the Office of Community Health and Safety.

As part of the pilot, Advanced Life Support EMS units will be able to administer buprenorphine to patients experiencing opioid withdrawal regardless if that patient decides to go to the hospital. Patients will then be able to schedule a virtual follow up with the UPMC Medical Toxicology Bridge Clinic to have a consultation with a doctor within 24 hours to get a buprenorphine prescription and be connected to other critical harm reduction resources.

Advanced Life Support EMS units will be able to administer buprenorphine to patients experiencing opioid withdrawal regardless of whether they decide to go to the hospital. Patients will then be able to schedule a virtual follow up to have a consultation with a doctor within 24 hours in order to get a buprenorphine prescription and be connected to other harm reduction resources.

The mayor of Pittsburgh, Bill Peduto, said: “The opioid epidemic has deeply affected so many cities and communities. If tools like buprenorphine exist, we need to have them in our communities and with our emergency medical personnel.” The Pittsburgh Post-Gazette reported there has been a 58% increase in overdose-related calls between October of 2020 and July of 2021—the latest month the city had data on. See the following chart showing the drug overdose calls to EMS in Pittsburgh.

Research shows that buprenorphine-assisted recovery from opioid use decreases the likelihood of recurrent overdoses and death from overdoses while increasing the likelihood of the person engaging in recovery. Dr. Jody Glance said buprenorphine helps patients more comfortably stop using opioids by alleviating their withdrawal symptoms. “Once the person is stabilized on the medication, they will not have the same level of cravings or desire to use illicit opioids.” This stabilization allows the person to engage in activities to support their ongoing recovery.

Dr Glance said some people remain on buprenorphine because they believe it is saving their life. “A lot of people find that the medication is so helpful, that coming off of it is more risky than staying on it.” She added that sometimes people stay on buprenorphine for a long time. Like other chronic, relapsing illnesses, “with opioid use, a lot of times people need a medication on a more long-term basis.” For patients who want hospital treatment, the program allows them to schedule a follow up visit with The UPMC Medical Toxicology Outpatient Clinic to continue taking the drug.

While it is an amazing, almost miraculous tool, bringing relative stability to the lives of opioid addicts, it comes with a price. Buprenorphine is itself an opioid. The DEA classifies it as a Schedule III controlled substance. It’s effectiveness in alleviating withdrawal and minimizing cravings for licit and illicit opioids is based on this pharmacological fact. And long-term use of buprenorphine perpetuates some of the same neurochemical actions found in opioid use disorder.

In her book, Never Enough, Judith Grisel introduced what she said were the three laws of psychopharmacology. They are: 1) all drugs act by changing the rate of what is already going on in the brain; 2) all drugs have side effects; and 3) the brain of someone who misuses drugs adjusts by producing fewer neurotransmitters in the reward circuit, or by reducing the number of receptors that can receive signals. The psychopharmacological action of buprenorphine-assisted recovery on the brain continues to activate these principles.

Not only do we need to bring stability to the lives of addicts after a nonfatal overdose, we need to educate them about the potential consequences they face with long-term use of buprenorphine. Inform them of the cost they’ll pay for a buprenorphine-assisted recovery.

For more information on Judith Grisel and the significance of the three laws of psychopharmacology to addiction recovery, see “Never Enough and No Free Lunch” and “Never Enough and Adaptation.”

09/8/20

Growing Pains with Narcotics Anonymous

Narcotics Anonymous (NA) rose up from the fragments of an earlier fellowship of the same name that had stopped holding meetings in the fall of 1959. The earlier NA, organized in 1953, struggled and ultimately could not overcome issues stemming from internal dysfunction and personality conflicts. In “Narcotics Anonymous: Its History and Culture,” William White, Chris Budnick and Boyd Pickard said that “NA as we know it today” learned lessons from the dangers of relying on a single dominant leader like Cy M., and of abandoning adherence to the Traditions of NA. They also needed to develop a distinctive culture for it fellowship, one that helped articulate the implications of inserting “our addiction” in the First Step instead of “alcohol.”

One of the first things Jimmy K., Sylvia W., and Penny K. did after rekindling NA meetings at Moorpark in late 1959 was to write new NA-based literature. Who Is an Addict?, What Can I Do?, What Is the NA Program?, Why Are We Here?, and Recovery and Relapse were all written in 1960. We Do Recover was added in 1961. These writings were gathered into a publication also published in 1962 called the Little White Booklet. Personal stories were added in 1966 and the White Booklet served as the center piece of NA literature until the Basic Text, Narcotics Anonymous, was published in 1983. See the NA World Services Recovery Literature page for copies of these and other pamphlets and booklets.

In 1972, NA Trustees looked at the idea of publishing a book similar to AA’s Big Book, but the plan did not get off the ground. It was not until 1977 when Bo S. began to pursue work on the Basic Text with the support of Jimmy K. that the idea became something more than just a thought. “The book was written between 1979 and 1982 over seven World Literature Conferences that involved over 400 recovering addicts in NA. NA’s Basic Text was approved in 1982 and officially released in 1983.”

Following the publication of the Basic Text, NA focused much of its publication efforts on It Works – How and Why, a collection of essays on the Twelve Steps and Twelve Traditions. Just for Today, a book of daily meditations, followed closely afterwards. Further efforts included a workbook on the Steps titled The Step Working Guide and a collection of sponsorship experiences simply called Sponsorship.

The Basic Text was the first substantial piece of literature created by addicts for addicts, and White, Budnick and Pickard said it marked the beginnings of NA’s own language and culture. NA growth had been progressing before the publication of the Basic Text, but after the release of the Basic Text, NA grew exponentially. There were five meetings by 1964, then 38 meetings in 1971, which grew to 3,382 meetings in 1983. This grew to 10,147 NA meetings by 1988, 16,575 by 1993 and 30,886 by 2003. In 2020, there are an estimated 71,000 NA meetings worldwide. See the following chart taken from “We Do Recover: Scientific Studies on Narcotic Anonymous.”

The presence of NA meetings in other countries also grew rapidly after the publication of the Basic Text. By 1968, there was a second country with NA meetings. In 1972, a third country was added and by 1983, there were 12 countries globally with NA meetings. By 1993 there were 60; by 2003, 106; by 2013, 129. There are an estimated 144 countries with NA meetings by 2020. NA literature is now available in 39 languages, with translations into 16 additional languages in process. In 2009, there were more NA meetings being held outside the US than in the US. See the following chart taken from “We Do Recover: Scientific Studies on Narcotic Anonymous.”Throughout much of its history, NA was in the shadow of its more well-known parent, AA. NA as we know it today, was founded by “bridge members” of AA (with dual addictions to alcohol and drugs). Its Steps and Traditions were drawn from those found in AA. Meeting formats, use of the Serenity Prayer and the Lord’s Prayer were copied from AA. But in the mid-1980s a large consensus emerged within the program that “challenged NA to step away from AA’s shadow and distinguish itself as a distinct recovery fellowship.” A 1985 communication from NA Trustees entitled, “Some Thoughts on Our Relationship with AA” acknowledged NA’s gratitude to AA. But it also noted its departure from AA in the language of NA’s First Step and then further elaborated on this divergence:

We are powerless over a disease that gets progressively worse when we use any drug. It does not matter what drug was at the center for us when we got here. Any drug use will release our disease all over again… Our steps are uniquely worded to carry this message clearly, so the rest of our language of recovery must be consistent with those steps. Ironically, we cannot mix these fundamental principles with those of our parent fellowship without crippling our own message.

The consensus begun in the 1980s has continued to grow and with it, the use of NA-specific language such as: addiction, self-identification as an addict, clean, and recovery from the disease of addiction. Meeting etiquette, terms and rituals are described in the NA pamphlet An Introduction to NA Meetings. There is an emphasis on solution-focused rather than problem-focused statements. Attention is placed on sustained NA service activity. And most importantly, there are NA members in long-term recovery who stay active in NA rather than disengaging or changing to another fellowship.

In “We Do Recover,” White and others said active drug users typically had a positive view of NA and sought help from NA through a variety of sources including an NA member (49%), referral by a treatment agency (45%) and encouragement from family members (32%). There was a strong association between NA participation and reduced drug use and increased rates of abstinence. The 2018 survey NA members reported an average of 11.4 years of continuous abstinence, with 85% reporting five or more years of stable recovery. But some friction has arisen with NA, and within NA regarding its stand on maintenance medications.

Attitudes and policies of NA towards the use of maintenance medications such as methadone, buprenorphine and naltrexone have been a source of tension within the NA fellowship and within the addiction treatment field, where medication-assisted treatment (MAT) is widely considered to be the gold standard treatment approach for opioid use disorder. Table 9 in “We Do Recover” summarized conclusions from various research studies of NA participation among individuals in medication-assisted treatment (MAT). Overall, they suggested NA involvement could be of potential benefit to people during MAT and as a source of post-MAT recovery support. But there are conclusions of a couple studies to take note of here.

Parran et al in “Long-term outcomes of office-based buprenorphine/naloxone maintenance therapy” conducted an 18-48 month follow-up study of opioid-dependent individuals and found that those who were still on buprenorphine/naloxone (bup/nx) at follow-up (85 of 110, 77%) were more likely to report abstinence from opioids and improvement on many quality of life measures. The major reason for discontinuing bup/nx maintenance was repeated evidence of substance use or the “failure to fully adhere with the abstinence based 12-step treatment.” White and others said the primary reason individuals discontinued medication maintenance in the study was the perceived incompatibility between MAT and 12-Step philosophy. But it seems to me another way of understanding why some individuals discontinued MAT was because they found themselves unable to maintain abstinence on MAT. Paran et al said: “Thus improved psychosocial functioning in bup/nx maintained patients was likely due to their marked decreased rate of substance use and not solely due to the bup/nx.”

There certainly is an incompatibility between MAT and NA 12-Step philosophy, but it was not clear if Paran et al tracked NA participation distinct from other 12-Step groups (which includes Methadone Anonymous, established in 1991), as they identified the 12 Step outcome variable as: “AA affiliated.” It was also not clear to me from their discussion if the researchers were even aware of how their blending of all 12 Step attendance into “AA affiliated” failed to distinguish this important nuance.

Monaco et al studied the effects of 12-Step participation on individuals treated for opioid dependence with buprenorphine in “Buprenorphine treatment and 12-step meeting attendance.” They found that despite the potential for philosophical conflicts between 12-Step groups and buprenorphine maintenance treatment (BMT), greater 12-step meeting attendance was associated with superior abstinence outcomes. In the six months after starting treatment, only 14% reported attending 5 or less NA meetings over the previous six months. However, only 33% reported disclosing their BMT status to an NA member. Of the participants who did disclose their BMT status, 26% reported that someone at NA encouraged them to stop taking buprenorphine or decrease their dose.

Qualitative data through semi-structured interviews of participants in the study indicated they were told by some in NA that the use of buprenorphine was a “crutch”; taking buprenorphine meant they weren’t “clean.” The typical view was that genuine clean time cannot be accumulated if you are taking buprenorphine, even if you are otherwise abstaining from all illicit drugs. Monaco et al said this presents a significant barrier for buprenorphine patients who find they benefit from both NA and BMT. But this conclusion failed to consider the historical context within which NA came into being. See “The Birth and Near-Death of Narcotics Anonymous” for more information on the origins of NA.

While this view may be a barrier, Monaco and others failed to acknowledge how buprenorphine has a dependency potential. It is not a neutral substance when it comes to how NA has historically unpacked “our addiction” in its First Step and described “the disease of addiction” in its literature. This means that NA is being implicitly asked to fundamentally blur how it defines being “clean” and confuse what it means by recovery from the disease of addiction. Pointing to the barriers MAT individuals encounter when they attend 12-Step groups and lamenting how they are stigmatized when told they aren’t “clean” (if they continue to use a MAT drug) seems to miss the point. The reality of buprenorphine and methadone as Scheduled substances with a defined abuse or dependency potential has to be acknowledged and addressed, but in most cases is ignored.

However, until that time, there are a couple of strategies identified by Monaco et al that can be used by BMT individuals who find value in attending NA meetings. The first one is to draw a clear, strong distinction between the use of buprenorphine and the abuse of other drugs. “This distinction is primarily based on two properties that separate BMT with substance abuse: 1) understanding buprenorphine medicinally, and 2) specifying the process of taking and acquiring buprenorphine through legitimate (and legal) channels.” Another strategy is to seek out 12-Step groups receptive to MAT, where there are others who take buprenorphine. This provides strength as a collective of similar others. “Despite the potential for philosophical conflicts between 12-step groups and BMT, greater 12-step meeting attendance during the first 6 months of treatment does not precipitate early treatment discontinuation and is associated with superior abstinence outcomes.”

The global expansion of NA has roughly paralleled the rise of the opioid epidemic and the addition of buprenorphine to the MAT arsenal in 2003. These three intertwined circumstances have intensified the debate over medication assisted treatment and recovery and seems to have immobilized our ability to move beyond the debate. Using rhetoric like “crutch” when referring to MAT users or saying the NA member who thinks someone who uses such language is “stigmatizing” perpetuates the polemic split of like-minded individuals into sides of medication haters and medication advocates. Even this distinction has a subtle categorization of individuals into the negative connotation of “haters” and the more sympathetic “advocates.”

William White, one of the coauthors of “Narcotics Anonymous: Its History and Culture” and “We Do Recover,” has tried for a long time to get a dialogue going between the pro-MAT and the anti-MAT groups. In an attempt to create that bridge, he wrote “From Bias to Balance: Further Reflections on Addiction Treatment Medications.” His advice there needs to be heard and acted on: “The key is our ability to objectively portray the potential value and risks of ALL treatment and recovery support options so that affected persons can make informed choices.” He called for rigorous, sustained personal, scientific and clinical investigation. “It also means that any initial distrust of medications from members of recovery communities should be respected by recovery advocates as grounded in the experiential knowledge of those communities.”

I think first there should be an acknowledgement of the value of buprenorphine as a treatment for opioid use disorder. There should be an investigation of its risks in MAT that begins by viewing buprenorphine through the lens of drug-centered action, as articulated by Joanna Moncrieff. Serious, sustained clinical investigation of the possibility of medically supported tapering for buprenorphine needs to be investigated. See the following articles for further interaction with William White’s “From Bias to Balance” and the application of Joanna Moncrieff’s thoughts to buprenorphine assisted recovery: “The Complexities and Limitations of Buprenorphine, Part 1” and “The Complexities and Limitations of Buprenorphine, Part 2.”

06/30/20

The Complexities and Limitations of Buprenorphine, Part 2

William White wrote “From Bias to Balance: Further Reflections on Addiction Treatment Medications” in an attempt to open a dialogue between the polarized sides of using opioid medications like buprenorphine to treat opioid addiction. In Part one of this article I expressed my belief that the impasse between the two sides is largely for philosophical, not scientific reasons. Medication advocates presume what Joanna Moncrieff calls a disease-centered model of drug action that leads to the belief and portrayal of certain medications as a panacea for opioid use disorders, something that the so-called medication haters soundly reject. I suggested that beginning instead with what Moncrieff calls a drug-centered model would allow for a more productive dialogue on the complexity and limitations of using buprenorphine to treat opioid use disorder.

In “Rethinking Models of Psychotropic Drug Action,” Joanna Moncreiff described the distinctions between two different types of drug action, the disease-centered model and the drug-centered model. She added that theoretical assumptions about how psychotropic drugs work are rarely discussed explicitly. The disease-centered model underlies orthodox psychopharmacology. It assumes that a psychotropic drug like buprenorphine helps correct a biochemical abnormality. In other words, medications are understood to work by acting on a disease process.

This notion, sometimes called the ‘chemical imbalance’ theory, is the explicitly stated view of SAMHSA, which says MAT medications (like buprenorphine) “relieve the withdrawal symptoms and psychological cravings that cause chemical imbalances in the body.” But in a ‘drug-centered model’ the distinctive physiological, behavioral and subjective effects of drugs are used to define drug action. “The therapeutic value of a drug stems from the usefulness of these effects in clinical situations.”

In this approach, drugs are seen to induce characteristic physiological and subjective states that may, or may not, be experienced as useful in certain social and interpersonal situations, including clinical situations. Unlike the disease-centred model that assumes that drugs move an abnormal physiological state towards a more normal one, the drug-centred model suggests that drugs create their own characteristic abnormal states or alterations of normal states. It is these states or effects that need to be described and understood, and the potential therapeutic value of a drug is deduced from this understanding. It is therefore implied that diagnosed patients and normal volunteers’ basic physiological responses to drugs will differ only in so far as a degree of individual variation in drug response (including variation in arousal, set, biological sensitivity) always exists.

Consistent with what Moncrieff said here regarding the drug-centered model, in “From Bias to Balance,” William White said the potential risks and benefits of medication support when treating opioid addiction are not uniform. He thought recovery advocates needed to have a general knowledge of the evolving science and the clinical experience with regard to the overall benefits and risks associated when medications like buprenorphine are used in medication-assisted treatment—what the side effects are, when and for whom it is indicated and contraindicated. “The question of potential degree of help or harm of medications in the treatment of addiction is unanswerable without also asking, ‘For whom?”’ ‘For what purpose?’, ‘For how long?’, and ‘At what cost?’.” White said that despite knowing that people recover from opioid addiction with and without medication support, the addiction treatment field still has not clinically defined who would benefit most from pharmacotherapy and for whom it would be contraindicated. He thought answering that question would be a major step forward.

The potential differences between those who achieve stable recovery (five years plus of opioid abstinence) from opioid use disorder through pharmacotherapy and those who achieve stable recovery without medication support are unclear. Nearly 40% of Narcotics Anonymous (NA) members report regular use of narcotics and an average of 8.2 years of continuous recovery. This would seem to challenge the bleak prospects of recovery from opioid addiction without medication support that dominates the professional literature and popular media. “Yet such recoveries from opioid use disorders within NA remain a rare focus of scientific study.”

There is also no consensus on the optimal duration of medication-assisted support in the treatment of opioid use disorder. SAMHSA said the length of time should be tailored to each patient and could be indefinite. In SAMHSA’s TIP 63, the section “Duration of Buprenorphine Treatment,” stated there was no known duration of buprenorphine therapy where patients could be certain they would not return to illicit opioid use. “Patients should take buprenorphine as long as they benefit from it and wish to continue.” ASAM, the American Society of Addiction Medicine, echoed SAMHSA’s indefiniteness, giving the following advice in their “National Practice Guideline” for the length of treatment with buprenorphine when treating opioid use.

There is no recommended time limit for treatment with buprenorphine. Buprenorphine taper and discontinuation is a slow process and close monitoring is recommended. Buprenorphine tapering is generally accomplished over several months. Patients and clinicians should not take the decision to terminate treatment with buprenorphine lightly.

Consistent with this reluctance to define or investigate a time limit for treatment with buprenorphine, William White said there has been inadequate attention to the process of tapering when clients choose to maintain their recovery without medication. The statistics reported in the research literature on those who attempt buprenorphine treatment are not promising. Meinhofer et al reported that over one-half (55%) of individuals discontinued buprenorphine within about six months and 13% experienced at least one adverse opioid-related event within 360 days of starting with buprenorphine. Hser et al reported that only 46% of buprenorphine participants completed 24 weeks of treatment; 24.8% dropped out within the first 30 days.

White stated the reality is that many patients who begin MAT for opioid addiction stop taking the medications within a matter of months. He cited a study of adolescents and young adults, “Receipt of Timely Addiction Treatment,” that found the median retention of those who did use buprenorphine was less than six months. Could it be that the intent to limit the risk of overdose mortality by leaving the time limit for MAT with buprenorphine open-ended has led to a perceived “Hotel California” effect in buprenorphine treatment? You can check in anytime you want, but you’ll find you can never leave. Open-ended treatment protocols like the SAMHSA and ASAM recommendations for buprenorphine leads abstinence-based recovery advocates and some addicts to conclude the goal is to keep patients “parked” on medication forever.

One factor influencing the open-ended recommendations for MAT is the high risk of overdose mortality when an opioid addict resumes active use. In the four weeks following the cessation of medication maintenance, death rates as high as four times that of patients who remain in treatment have been reported, due to the lost tolerance from their abstinence. This parallels the risk of overdose mortality after the release from a prison, hospital or inpatient/residential addiction treatment program.

One of White’s suggested action steps was to expand supports available for patients during and after medication tapering. According to ASAM, factors associated with the successful termination of treatment with buprenorphine are not well described, but may include the following:

Employment, engagement in mutual help programs, or involvement in other meaningful activities.
Sustained abstinence from opioid and other drugs during treatment.
Positive changes in the psychosocial environment.
Evidence of additional psychosocial supports.
Persistent engagement in treatment for ongoing monitoring past the point of medication discontinuation. Patients who relapse after treatment has been terminated should be returned to treatment with buprenorphine.

White said long-term follow-up studies of people with opioid use disorders find that between a third and half of those who achieve stable recovery have far less problem severity and complexity and have great recovery capital (e.g., education, employment, family and social support).

The overwhelming majority of addiction medication providers assert the value of psychosocial interventions as a critical component of addiction treatment, but little more than a third report that their organizations and local communities have the resources to provide such interventions for patients using medication to support recovery from an opioid disorder.

A final complexity and limitation with buprenorphine as an opioid medication is that buprenorphine is itself an opioid. Given Moncrieff’s drug-centered model of medication action, this reality needs to be acknowledged by treatment professionals and addressed when evaluating the overall benefits and risks of buprenorphine. The potential degree of help or harm it may incur should also be discussed honestly and openly with the individual. One of the likely effects an individual should expect when tapering off of buprenorphine is the emergence of a withdrawal or discontinuation syndrome.

In Part 1 of this article, I discussed how according to the drug-centered model, when psychoactive medications like buprenorphine are taken over a long period of time, they “induce physical adaptations to the presence of the drug.” The body attempts to counteract the effects of the drug, which it sees as a foreign, exogenous substance. In time, a kind of homeostasis is reached between the effects of the medication and the body’s adaptations to it. When the medication is stopped, the body’s adaptations overpower the now weakened medication effect and symptoms of withdrawal or discontinuation are evident. I’d suggest this is likely with years of medication maintenance and even after a slow, gradual taper.

The taper event should be addressed clinically as a relapse trigger and the resulting withdrawal symptoms understood simply as that; and not as a reemergence of the ‘disease state’ that will lead back to active use if buprenorphine maintenance is not resumed. I think this discontinuation or withdrawal is best understood as the delayed manifestation of post-acute withdrawal (PAW) symptoms. The original use of an opioid recreationally was supplanted by an opioid (buprenorphine) used as a MAT and the original emergence of PAW symptoms was muted or never truly occurred.

I’ve added the thinking of Terrance Gorski on recovery and relapse to the discussion here. See “Preventing the Relapse Process,” Part 1 and Part 2 for a discussion of relapse. See “Managing Your PAWS” and “Recognizing Your PAWS” for a discussion of post-acute withdrawal. Also see the Gorski-CENAPS Corporation for his books and workbooks.

I think there can be productive dialogue between the two opposing views of medication-assisted treatment. A necessary first step is to see buprenorphine and opioid use disorder through the lens of the drug-centered model of medication action. Then there can be discussions of the complexities and limitations of treating opioid use disorder with an opioid. Research won’t have to ignore that elephant in the methodology. And then we can begin to do the truly important work of answering the questions—for whom, for what purpose, for how long and at what cost—as we assess the potential help or harm of buprenorphine as a treatment for opioid use disorder.

06/23/20

The Complexities and Limitations of Buprenorphine, Part 1

William White said he has for years tried to build bridges of communication across the polarized debates surrounding the use of medications in the treatment of addiction. He wrote “From Bias to Balance: Further Reflections on Addiction Treatment Medications” with a two-part goal in mind that I have borrowed and revised to frame my discussion here regarding the use of buprenorphine to treat opioid use disorder. The first part of White’s goal in “From Bias to Balance” was to help recovery advocates understand the positions of some who reject the use of medications as a pancea for opioid use disorders. The second part was to understand the complexities and limitations involved in the use of buprenorphine to treat opioid use disorders. For what it’s worth, I think I largely agree with White, even if I approach the issue more from the side of abstinence-based recovery.

Seeing medication-assisted treatment (MAT) as a polemic of medication haters and medication advocates muddies the waters by lumping different medications with radically different effects into the same category of MAT. According to SAMHSA in “Medication and Counseling Treatment,” the FDA has approved methadone, buprenorphine and naltrexone to treat opioid use disorder. Both methadone and buprenorphine are themselves scheduled substances by the DEA, meaning they each have a potential for misuse. This should be kept in mind when they are used to treat opioid use disorder, and be seen as a limitation of the respective medication. The other FDA-approved medications used for MAT, including those used to treat alcohol use disorder, are not scheduled substances and do not have the same limitation.

SAMHSA said a common misconception with MAT is that it substitutes one drug for another. According to SAMHSA, these medications are said to relieve the withdrawal symptoms and psychological cravings “that cause chemical imbalances” in the body. The phrase, “that cause chemical imbalances,” implies that the medications help correct an abnormal brain state, an assumption of what psychiatrist Jonanna Moncrieff called the disease-centered model of drug action in The Myth of the Chemical Cure. Buprenorphine and methadone do not balance or correct an abnormal brain state, in my opinion. They are as much exogenous, foreign bodily substances, as heroin or fentanyl are. I think Moncrieff’s alternative model, the drug-centered one, more appropriately captures both the effects of the originally misused drug and the medication used to treat it.

Joanna Moncrieff developed her drug-centered and disease-centered models of drug action to describe how psychiatric medications work, but they also apply to all psychoactive substances, all mind-altering and mood-changing chemicals. The disease-centered model of drug action seems to underlie the uncritical advocacy of medications for opioid use disorders. “Psychiatric drugs [including methadone and buprenorphine] are psychoactive drugs which, by their neurophysiological effects alter ‘mental and emotional life and behaviour for the duration of the treatment.’” Along with their immediate and sometime euphoric effects, when psychoactive medications are taken over a long period of time on a regular basis, they “induce physical adaptations to the presence of the drug.” These adaptations have several consequences, including the following.

When a psychoactive medication is used on a regular, frequent basis, the body attempts to counteract the effects of the drug, which it sees as an invading, foreign substance. In time, a kind of homeostasis is reached between the effects of the psychoactive medication and the body’s adaptations to it. This often leads to the development of tolerance, meaning that larger doses of a medication are needed to achieve the original psychoactive effects. When the medication is stopped or reduced too rapidly, the body’s adaptations overpower the weakened or absent medication effect and symptoms of withdrawal or discontinuation become evident.

When this process is viewed through the lens of a disease-centered perspective, the body’s reaction is interpreted as evidence of the reemergence of the underlying condition which the medication had “balanced.” In this case, opioid use disorder. And the recommended treatment is then a continuation of the psychoactive medication to maintain that balance, perhaps indefinitely. Instead of a disease-centered view of restoring chemical balance, I think opioid medications like methadone and buprenorphine relieve withdrawal symptoms and psychological cravings by creating their own abnormal brain state. This view is consistent with Moncrieff’s drug-centered model of drug action.

See “A Drug Is a Drug Is a Drug” or search this website for “the disease-centered model” for more on this topic. Also see “Models of drug action” on Jonna Moncrieff’s blog and “Rethinking Models of Psychotropic Drug Action.” Nevertheless, as William White said, medications can play a valuable role in addiction treatment:

Medications can play a valuable role in harm reduction, recovery initiation, and recovery maintenance for populations for whom they are indicated and acceptable, but we do a disservice to those populations, their families, and their communities if we portray medication alone as a panacea for the cure of all opioid addiction and fail to carefully communicate both the potential value and the limitations of medications. Issues like the above [see “From Bias to Balance”] need to be part of our nuanced discussions with those we serve. We similarly do a disservice if we let anti-medication polemics go unchecked within our local and national conversations.

Medications are best viewed as an integral component of the recovery support menu rather than being THE menu, and their value will depend as much on the quality of the milieus in which they are delivered as any innate healing properties that they possess. If the effectiveness of medication-assisted treatment (MAT) programs is compromised by low retention rates, low rates of post-med. recovery support services, and high rates of post-medication addiction recurrence, as this review suggests, then why are we as recovery advocates not collaborating with MAT patients, their families, and MAT clinicians and program administrators to change these conditions?

People seeking recovery from opioid use disorders and their families are in desperate need of science-grounded, experience-informed, and balanced information on treatment and recovery support options—information free from the taint of ideological, institutional, or financial self-interest.

Consistent with a drug-centered model of medication action, the potential risks and benefits of buprenorphine as a MAT need to be objectively and scientifically assessed. One of the complexities and a limitation of buprenorphine-based MAT is the fact that it is a Schedule III controlled substance, with a moderate to low potential for physical and psychological dependence. There is also a higher risk of harm, including overdose and death, when buprenorphine is combined with benzodiazepines or other sedatives like alcohol. Because of this danger, information was added to the Boxed Warning on the Medication Guides by the FDA for buprenorphine products on the risks of slowed or difficult breathing and death. Even before it was approved as a MAT, in the US, buprenorphine was known to have problems with diversion and misuse.

While the risks of misuse are lower for buprenorphine than for most other opioids in the US, this is not true in many European and Asian countries. Illicit buprenorphine use has been reported in Sweden, Scotland, Norway, Ireland and Spain. In Finland buprenorphine is the most widely abused opioid. In 2001 Finland had a sharp increase in the misuse of buprenorphine that coincided with a decrease in the availability of heroin. Seventy-three percent of a sample of participants in a Finnish syringe exchange program reported buprenorphine was their most frequently abused injection drug. Participants also used it as a self-treatment for withdrawal.

In “From Bias to Balance,” William White noted the standard practice with medications is to define the precise condition a medication is best suited to treat, and then identify patients who should not be prescribed the medication because of potential harm, meaning the risks outweigh the potential benefits for them. Yet after more than a century of attempts to treat opioid addiction with medications, there is no clinically defined protocol for who is most likely to benefit from pharmacotherapy. Additionally, “the question of potential degree of help or harm of medications in the treatment of addiction is unanswerable without also asking, “‘For whom?’ ‘For what purpose?’, ‘For how long?’, and ‘At what cost?’.”

White said the addiction treatment field has yet to reach consensus on what is the optimal duration of medical support in treatment of opioid use disorder. I think this impasse partly reflects the unacknowledged presumption of Moncrieff’s disease-centered model of drug action among medication advocates. The disease-centered model is itself a product of what is called the medical model, which sees psychopathology as the result of biology; a physical/organic problem in brain structures, neurotransmitters, etc. The over reliance on the medical model perspective (and the disease-centered model of drug action) in addiction treatment leads to an imperfect conception of substance use disorder and a distorted understanding of the risks and benefits of buprenorphine when it used to treat opioid use disorder.

Self-consciously taking a drug-centered model of drug action with buprenorphine and rejecting the medical model perspective of substance use disorders is necessary to truly reach a consensus on the potential degree of help or harm of buprenorphine in the treatment of opioid addiction. Consider what Joanna Moncrieff said in The Myth of the Chemical Cure when contrasting her two models of drug action to the use of buprenorphine in MAT:

The disease-centred model suggests that the important or ‘therapeutic’ effects of drugs are achieved by their effects on a particular disease process. By acting on the mechanisms of the disease, drugs move the human organism from an abnormal physiological state towards a more normal one. In contrast, the drug-centred model suggests that drugs themselves create abnormal bodily states. In the case of drugs that act on the brain or the nervous system, these states involve an alteration in subjective experience or consciousness. Psychiatric drugs [including buprenorphine, I would add] are psychoactive drugs which, by their neurophysiological effects alter ‘mental and emotional life and behavior for the duration of the treatment’ (Cohen & Jacobs 2007). When we consider drugs that are taken recreationally we have no trouble recognizing this fact and we refer to the altered mental state drugs produce as ‘intoxication’. But there is no fundamental distinction between drugs used for psychiatric purposes and other psychoactive drugs. They all act on the nervous system to produce a state of altered consciousness, a state that is distinct from the normal undrugged state.

The impasse between so-called medication haters and medication advocates is philosophical, not scientific. Beginning with a drug-centered model of buprenorphine can help us move forward in correctly addressing questions on the potential degree of help or harm buprenorphine brings to the treatment of addiction. We can more clearly discuss the complexity and limitations of using buprenorphine, an opioid medication, to treat opioid use disorder when that treatment is viewed through a drug-centered model of medication action.

12/31/19

Keeping ALKS 5461 Out of the Spotlight?

Alkermes has been stubbornly attempting to gain FDA approval for ALKS 5461 as an adjunctive treatment for major depression. After the FDA informed Alkermes it was refusing to review the NDA (New Drug Application) for ALKS 5461 on March 30, 2018, it rescinded its refuse-to-file letter, and said it would review an NDA for ALKS 5461. The target action date was set for January 31, 2019. The Chief Medical Officer at Alkermes noted there have been no new pharmacological treatment approaches for depression in 30 years and said, “FDA’s filing of the ALKS 5461 application is a positive step forward for patients suffering from major depressive disorder.”

Strategically, at the end of October 2018 Molecular Psychiatry published an article that indicated buprenorphine/samidorphan (ALKS 5461) was “a promising potential adjunctive treatment for patients with MDD.” In one clinical trial, FORWARD-5, adjunctive ALKS 5461 (BUP/SAM 2mg/2mg) consistently reduced depression symptoms compared to placebo across multiple timepoints in patients continuing their current antidepressant therapy (ADT). And it met the primary endpoints of reducing core and overall depression symptoms. In the previous FORWARD-4 clinical trial the primary endpoint of change was not statistically significant; it failed to meet its primary endpoint of change. But in post hoc analysis it did demonstrate greater reduction in MADRS-10 scores than placebo at all timepoints in both stages. “Reductions in symptom scores at multiple timepoints are consistent with the observed efficacy in FORWARD-5.”

This post hoc-analysis was bit like cheating, in that it reanalyzed the data from FORWARD-4 after the fact, and found one aspect of the trial with a significant result. Alkermes used the finding to “update” their methodology for FORWARD-5 to match the post-hoc analysis. It then attempted to argue that despite failing to meet its primary endpoints in the two previous phase III clinical trials, the FDA should approve ALKS 5461. See “The ‘Hotel California’ Effect” and “Nearsighted Drug Development” for more on the problems with this process.

Then on November 1, 2018 the results of the meeting of two combined FDA committees, the Psychopharmacologic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee was released. The Committee voted unfavorably for ALKS 5461. There were three core questions. Has there been substantial evidence presented to support the effectiveness of ALKS for adjunctive treatment of major depression? The vote was against the first question, 20 to 3. The second question was: Has Alkermes adequately characterized the safety profile of ALKS 5461 for adjunctive treatment of major depression? The vote was for the question, 13-10. The third question was also answered negatively, Do the data show a favorable benefit-risk profile of ALKS 5461 to support approval? The vote was against, 21 to 2.

Healio Psychiatry went on to note several concerns of the Committee. The FDA did not agree with Alkermes that the studies met the standard for substantial evidence for effectiveness. Three of the studies used a novel study design: a 2-stage, sequential parallel comparison meant to reduce the higher placebo response often seen in antidepressant studies. This was the first time a sequential parallel comparison design was submitted to the FDA to provide evidence of efficacy for a new drug. “This design has not yet been determined to be statistically acceptable to the FDA.”

Usually studies for antidepressant treatments examine an efficacy endpoint at a specific time point following several weeks of therapy, according to the FDA. These trials achieved primary endpoint because researchers averaged patients’ depression symptoms over multiple weeks, which is not standard for antidepressant trials. Although averaging scores from multiple weeks can reduce the symptom changes that often vary over time throughout treatment, scores at the final time point carry less weight.Although one of the phase 3 studies met its primary endpoint, the committees expressed worry because the trial investigators used an abridged 6-item version of the Montgomery Asberg Depression Rating Scale-10 for the primary endpoint of this principal study. The FDA’s Clinical Outcomes Assessment staff believe MADRS-6 cannot replace the MADRS-10 because it excludes concepts important in major depression, like reduced sleep, reduced appetite, concentration difficulties and suicidal thoughts, according to the review.

So MADRS-6 would not include data on the excluded depressive symptoms such as reduced sleep, and appetite, concentration problems, and significantly, suicidal ideation. Averaging scores would hide a pattern of progressively lower scores throughout the trial, suggesting the antidepressant effect of ALKS 5461 gets weaker over time and will eventually be no better than placebo—not the efficacy pattern to demonstrate when trying to have a NME approved by the FDA. Given the novelty of the methodology used in these clinical trials and the significance of the excluded depression symptoms, the FDA made it clear to Alkermes that any studies using the MADRS-6 would be “considered exploratory.”

The use of an opioid, buprenorphine, was also a concern of the committee. Given the growing opioid epidemic, there were concerns about use, misuse and abuse of buprenorphine. Predicting what might happen in patients being treated for depression is challenging due to the high-risk nature of the populations being treated. “It is not known whether similar misuse and abuse patterns will be seen.”

Finally on February 1, 2019, the FDA said it was not able to approve ALKS 5461 in its present form and requested additional clinical data (likely another clinical trial) to provide substantial evidence for its effectiveness. A review of the Alkermes website on October 12, 2019 failed to see ALKS 5461 listed in its Pipeline under Research and Development. But that doesn’t mean Alkermes has given up on it. There are two active clinical trials for ALKS 5461 listed on Clinical Trials.gov; one of which is recruiting. Its primary outcome measure is a change from baseline in the MADRS scores; the time frame is 11 weeks. The other trial is by invitation, and is a long-term study. The time frame is up to 68 weeks. Both are projected to be completed in 2021 and both have been updated after the FDA sent its complete response letter on February 1^st.

It could be that Alkermes terminated these clinical trials after the FDA response letter, but why update the information on ClinicalTrials.gov? If Alkermes is still working on the studies, why does it not have ALKS 5461 listed in its Pipeline? It does not seem that ALKS 5461 is dead yet. One of the studies (clinical trial NCT03188185) apparently plans to use the same parallel assignment method used in FORWARD-4, which the FDA said it had not yet determined was statistically acceptable. The MADRS will be used for its primary and secondary outcome measures, but does not specify whether it will be MADRS-6 or MADRS-10. One of the listed outcome measures is the Columbia Suicide Severity Rating Scale, for suicidal ideation and behavior, but that isn’t necessarily suggestive Alkermes plans to use the MADRS-6.

It is possible that Alkermes is going ahead with a final attempt to gain FDA approval for ALKS 5461, but is trying to keep its efforts quiet and out of the media spotlight. We’ll have to wait and see.

12/3/19

The Pied Pipers of Suboxone

Reckitt Benckiser, the company that brought Suboxone to market, settled allegations that the company wrongly marketed and promoted Suboxone, resulting in the improper expense to state Medicaid funds. Reckitt will pay $700 million to settle the allegations. New York State Attorney General, Letitia James, said in a release dated October 23, 2019, that no company is above the law: “Reckitt misled the public about the real impacts of Suboxone and encouraged physicians to wrongly prescribe it, while cheating New York out of tens of millions of dollars in the process.” FiercePharma reported that would bring Reckitt total settlements this year to just over $2 billion, putting its Suboxone marketing investigations behind it, once and for all.

On April 9^th 2019, a federal grand jury indicted Indivior, formerly part of Reckitt Benckiser Pharmaceuticals Inc., for allegedly engaging in an illicit nationwide scheme to promote Suboxone. Reckitt Benkiser had spun off Indivior Inc., meaning the two became separate companies in December of 2014. The U.S.’s criminal trial against Indivior is scheduled to begin on May 11, 2020. Then the U.S. Department of Justice announced on July 11, 2019 that Reckitt Benckiser agreed to pay $1.4 billion to resolve potential criminal and civil liability related to a federal investigation of the marketing of Suboxone.

After the April 9, 2019 indictment against Indivior, FiercePharma reported the company said the allegations were “wholly unsupported by either the facts or the law.” Indivior’s Chairman said the company “never deliberately diverted its product.” In an open letter he claimed the company went beyond what the law required in its education campaign to doctors and by reporting multiple physicians to the appropriate authorities. He further claimed the DOJ indictment can’t be justified on any fair reading of the facts or the law. “But we will contest these charges vigorously and we are confident in our position.”

It is not clear if Indivior is as confident in its position following the DOJ announcement. “RB Group has agreed to cooperate fully with all investigations and prosecutions by the Department of Justice related, in any way, to Suboxone.” Indivior may find it is fighting against the interests of its former parent company, Reckitt Benckiser. The DOJ said:

According to the indictment, Indivior—including during the time when it was a subsidiary of RB Group—promoted the film version of Suboxone (Suboxone Film) to physicians, pharmacists, Medicaid administrators, and others across the country as less-divertible and less-abusable and safer around children, families, and communities than other buprenorphine drugs, even though such claims have never been established.The indictment further alleges that Indivior touted its “Here to Help” internet and telephone program as a resource for opioid-addicted patients. Instead, however, Indivior used the program, in part, to connect patients to doctors it knew were prescribing Suboxone and other opioids to more patients than allowed by federal law, at high doses, and in a careless and clinically unwarranted manner.The indictment also alleges that, to further its scheme, Indivior announced a “discontinuance” of its tablet form of Suboxone based on supposed “concerns regarding pediatric exposure” to tablets, despite Indivior executives’ knowledge that the primary reason for the discontinuance was to delay the Food and Drug Administration’s approval of generic tablet forms of the drug.The indictment alleges Indivior’s scheme was highly successful, fraudulently converting thousands of opioid-addicted patients over to Suboxone Film and causing state Medicaid programs to expand and maintain coverage of Suboxone Film at substantial cost to the government.

Meanwhile, as alluded to above in the above news release from the DOJ, Indivior has been fighting a legal battle to delay generic approval for Suboxone. On June 14, 2018, the FDA approved Mylan Technologies Inc. and Dr. Reddy’s Laboratories SA to market the first generic versions of buprenorphine and naloxone sublingual film (Suboxone). Then on June 15^th, the U.S. District Court of New Jersey granted Indivior a temporary injunction against Dr Reddy’s, compelling it to immediately stop its launch activities with Suboxone film. According to FiercePharma, Indivior has filed patent infringement lawsuits against both Mylan and Dr Reddy’s. Indivior will have to pay Dr Reddy’s $18 million to satisfy losses or damages incurred during the temporary restraining order if the generics company is successful in its legal defense.

When the U.S. Court of Appeals found that Indivior was not likely to succeed on the claimed patent infringement and ruled the lower court’s preliminary injunction be lifted, Indivior then tried blocking the appeals court ruling by taking the issue to the Supreme Court. Chief Justice John Roberts denied Indivior’s motion to stay the appeals court mandate on February 19^th, 2019, clearing the way for Dr Reddy’s to market its generic version of Suboxone as the litigation continues. Dr Reddy’s immediately began shipping its generic version, as the original injunction did not stop it from manufacturing the drug. Indivior then announced it would launch its own generic version of Suboxone in the U.S. on February 20^th. Mylan, which had made a deal with Indivior, announced it will launch its generic version on February 22^nd.

Then on July 12, 2019, the U.S. Federal Circuit Court of Appeals in Washington upheld lower court rulings that “Dr. Reddy’s did not infringe two Indivior patents related to Suboxone.” Two other companies, Teva and Alvogen were also found to not have infringed on Indivior patents. Writing for the majority, Circuit Judge Alan Lourie said that while Indivior’s patents should not be voided, it failed to show that they covered Dr. Reddy’s and Alvogen’s drying processes for their products. This was the day after Reckitt Benckiser agreed to pay $1.4 billion to settle a federal investigation of the marketing of Suboxone noted above. Indivior said the settlement was separate from its own case.

The above consequences have been coming for several years. And Reckitt Benckiser and Indivior are complicit in the actions taken by both companies to position themselves as the primary service provider for buprenorphine-based MAT in the U.S. But their actions to delay generic buprenorphine/naloxone didn’t just begin during the time period described above.

Reckitt Benckiser (RB) knew it only had patent exclusivity for their buprenorphine products (Suboxone and Subutex tablets) until 2009, but they had a strategy to circumvent the pending loss. First, they acquired the rights for the sublingual film version of Suboxone in 2008. Then in October of 2008 they submitted a New Drug Application to the FDA for the film version of Suboxone, which was approved by the FDA in August of 2010.

In its 2011 annual report, Reckitt Benckiser thought generic versions of Suboxone could take up 80% of the revenue and profit from the U.S. Suboxone market. However, they expected Suboxone film would help “to mitigate the impact.” Then in September of 2012 RB announced that they were voluntarily withdrawing Suboxone tablets from the market because of data they had received from the U.S. Poison Control Centers suggesting there were higher rates of pediatric overdose on the tablet formulation than the film version. The FDA thought the study Reckitt Benckiser cited (and paid for) did not demonstrate any difference in its safety profile of abuse formulations between Suboxone tablets and film.

Public Citizen said that few, if any, companies went as far as RB to pre-emptively withdraw an off-patent drug from the market (Suboxone tablets) to make room for a newly patented successor (Suboxone film). A year before the withdrawal of the tablets from the market, RB stated in its 2011 report that its goal was to convert as many tablet users as possible to the film version.

To this end, the company initiated a marketing campaign to persuade physicians to switch patients from the tablet to film form. It also employed more direct tactics to complement the marketing push, raising the price of the tablets to levels higher than the film versions. As a result of these efforts, tablet sales fell 19 percent between August 2011 and August 2012, while sales of Suboxone film doubled during the same period. By September 2012, the film version had captured 70 percent of the Suboxone market, clearing the way for the announcement of the withdrawal of the tablets that month. See “The Opioid Buzzard” for more on this.

Whether you look at Reckitt Benckiser or Indivior you can see a pattern of systematic steps to maintain a monopoly on the buprenorphine-naloxone end of the MAT, medical-assisted treatment, market. This resulted in 2019 with over $2 billion in settlements for improper, illegal marketing tactics with Suboxone for Reckitt Benckiser. Indivior is next, as the federal government indicted it for an illicit scheme to market Suboxone. Yet Indivior still projects a rosy future for its products. It has a new buprenorphine product, monthly depot shot of buprenorphine called Sublocade, and Perseris, which is an extended release injectable of risperidone for schizophrenia that launched in February of 2019. But there are additional changes in the MAT market that contribute to Indivior’s optimism.

The first quarter financial report by Indivior for 2019 reported that U.S. net revenue grew 2% as Suboxone Film share loss was more than offset by “underlying market growth, strong initial sell-in of the Group’s authorized generic film product and net revenue from SUBLOCADE™.” Operating Highlights for the first quarter included continued growth of the U.S. buprenorphine market, driven primarily by Government channels. The share erosion since the “at risk” launch of generic buprenorphine/naloxone film products in February 2019 was lower than anticipated. Suboxone Film market share ended the quarter with a 53% market share. “Sandoz Inc. launched an Indivior authorized generic buprenorphine/naloxone film and captured the leading position among allgeneric film products” by the end of the first quarter. Shaun Thaxter, the CEO of Indivior, said their first quarter performance only strengthened their confidence that they are “putting the building blocks in place for a return to sustained growth” with Sublocade and Perseris. He looked forward to reporting progress throughout the year.

His optimism seems to rest on how the market for buprenorphine products continues to grow, benefitting from legislative changes that have expanded opioid use disorder (OUD) treatment funding and treatment capacity. This was accomplished by increasing the number of patients that physicians could treat from 100 to 275.

Recognising the foregoing factors, we are introducing FY 2019 financial guidance. A key element of guidance is of course the performance of SUBLOCADE™, our new monthly buprenorphine extended-release injection, and here we made good progress in executing our plans: Q1 net revenue of $11m puts us on track to meet our FY 2019 guidance for net revenue of $50m-$70m. We continue to believe SUBLOCADE™ to be a transformational treatment for opioid dependence and we will not be distracted in our efforts to bring this important new option to patients in the US. Separately, while not a material contributor to our full-year guidance, we are nonetheless encouraged by the initial market reception to PERSERIS™, our monthly risperidone injection for schizophrenia, which we launched towards the end of the first quarter.

Thaxter said Indivior remained “undaunted in the pursuit of our Vision to improve the lives of patients suffering from addiction and its co-occurring disorders.” Yet the above story seems to point to another Vision—sustained growth and profitability—that blinds them from seeing where they are potentially taking us. Is this self-described “leader and innovator” in OUD treatment leading towards a “treatment” strategy that increases rather than decreases the number of those who are chained to an opioid? Like in the story of the Pied Piper, are we dancing to the tune of Indivior, unaware we are being led into the river of OUD instead of being saved from it?

For more on Indivior and Sublocade, see “Opioid Epidemic Price Gouging.” For further information on Reckitt Benckiser and its attempts to prolong a market for Suboxone, see “A Double-Edged Drug.”

12/4/18

The Bondage of Buprenorphine

It’s not often that a patent award creates a media storm, but it happened recently when a patent was awarded for a novel oral formula of buprenorphine, the opioid in Suboxone and its generic cousins. The new formula is a buprenorphine-wafer that is proposed for MAT (medication assisted therapy) with opioid addicts as well as for treating chronic pain. The wafer formula is said to be more “diversion and/or abuse-resistant” than the existing ones, which are tablets (ie., Subutex and Zubsolv) and sublingual film (i.e., Suboxone). It just so happens that one of the six listed inventors of the buprenorphine wafer is Richard Sackler; and Purdue Pharma LP was the original assignee for the patent. Members of the Sackler family and Purdue Pharma are currently facing hundreds of lawsuits that claim they played a role in the birth and growth of the opioid crisis.

The connection of the Sackler family and Purdue Pharma to the opioid crisis is tellingly documented by Barry Meier in his book, Pain Killer, which was recently released in a second, updated edition. Read: “Giving an Opioid Devil Its Due” for an overview of Meier’s book, with links to two NYT articles he wrote as Pain Killer was published in May of 2018. Also see “The Tale of the OxyContin Lie,” “Greed with OxyContin is NOT Good,” and “Doublespeak in the Opioid Crisis, Part 2” for more on the connection of Purdue Pharma and the Sackler family to the opioid crisis.

Among the media outlets describing the Sackler and Purdue connection to the buprenorphine-wafer patent was STAT News and The Washington Post. Both news outlets noted how several critics are outraged that the Sacklers and Purdue are positioning themselves to benefit financially from the opioid epidemic they are seen as having facilitated in the first place. Luke Nasta, the director of a New York-based drug and alcohol addiction treatment center said the Sackler family “shouldn’t be allowed to peddle any more synthetic opiates—and that includes opioid substitutes.” He added: “It’s reprehensible what Purdue Pharma has done to our public health.”

The patent application for the buprenorphine-wafer said there is a need for “other diversion and/or abuse-resistant dosage forms of buprenorphine, which can be used in drug substitution therapy.” Additionally, the preparation would also provide “efficient analgesia” when used for pain relief.

It is an object of the present invention to provide an oral pharmaceutical dosage form of the active agent buprenorphine that is less prone to diversion and/or abuse in drug substitution therapy. It is another object of the present invention to provide an oral dosage form of the active agent buprenorphine that can be used for drug substitution therapy and/or pain treatment.

The patent does not seem to only envision using the wafer technology with buprenorphine. It points out how “the invention and its various embodiments which are set out below, can be extended to any opioid or analgesic whose preferred route of administration is oral, preferably sublingual, as is the case for buprenorphine.” One embodiment of the wafer is also said to release buprenorphine or other “pharmaceutically acceptable salt” in less than three minutes, and perhaps as quickly as one or two minutes.

Even more preferably, substantially all of the buprenorphine or said pharmaceutically acceptable salt thereof will be released within less than thirty seconds, twenty seconds, ten seconds or even within less than five seconds after oral, preferably sublingual, application of the dosage form.

Reflect for a moment on how rapid, “instant” absorption of a drug intravenously or nasally is often the preferred method of drug ingestion by an addict because the euphoria is more immediate. The good news here is the wafer technology will seemingly restrict diversion, but the bad news is it may initiate another rapid ingestion method for individuals looking for an opioid high. The biochemical nature of buprenorphine is said to have a “euphoric ceiling” that limits its long-term abuse potential, but the same is not true for other addictive “pharmaceutically acceptable salts.”

Another red herring in the patent application is describing how drug addicts take prescription drugs for replacement therapy “under the close supervision of medical parishioners.” This means that the slower absorption of buprenorphine in the other formulas, taking five to ten minutes to dissolve, could result in drug addicts trying “to divert these sublingual buprenorphine tablets by removing them from the mouth when the supervising healthcare professional’s attention is directed to other activities.” Methadone, which is only used within a medical setting in the U.S., did have these kinds of problems years ago so the formula was changed from a tablet to a liquid form. Ingesting buprenorphine in MAT is NOT supervised in a medical setting in the U.S. The patient gets a prescription and takes the medication without any medical supervision, so the supposed advantage of the rapidly absorbed buprenorphine wafer in limiting diversion is nonexistent.

Also in the news about the Purdue Pharma debacle is the role of Rudy Giuliani, who acted as legal counsel for Purdue in the mid-2000s. FiercePharma, The Hill and others reported that two Democratic Senators are requesting documents detailing information about Purdue Pharma’s interactions with the Department of Justice and the Drug Enforcement Agency when Purdue was under investigation for its OxyContin promotions. They are trying to determine whether or not Giuliani “secured leniency for opioid maker Purdue Pharma through conflicts of interest.” At the same time he was representing Purdue Pharma in its dealings with the Department of Justice over a probe of Purdue’s marketing of OxyContin, Giuliani’s firm worked for the DOJ under a $1 million contract to provide advice on reorganizing its major drug investigations. FiercePharma said:

According to the letters, Giuliani convinced political appointees at the Department of Justice to reject career prosecutors’ recommendations in the opioid marketing case. As a result, the company entered a guilty plea to “misbranding” OxyContin, its powerful painkiller. Under the deal, the senators also said Giuliani convinced DOJ to assign fault to Purdue Frederick, a holding company, to allow Purdue Pharma to continue to do business with the federal government. Purdue paid $640 million under the agreement in 2007.

The bottom line is it seems Giuliani helped Purdue keep OxyContin on the market after 2007. Top Justice Department officials in 2006 failed to follow their Virginia prosecutors’ recommendations to indict Purdue Pharma executives on felony charges instead of the lesser misdemeanor charges and no jail time they ultimately received. Even with this sweet plea deal in hand, the night before the plea agreement was set to expire—meaning the company would face charges—a senior Justice Department official (“at a Purdue lawyer’s request”) phoned John Brownlee, the U.S. Attorney pursuing the indictment, at his home in an attempt to convince him to extend the deadline and give Purdue more time. It didn’t work.

By the time the negotiations were complete, Purdue’s holding company, Purdue Frederick, would plead guilty to a single misbranding felony and the company’s executives to misdemeanor charges of misbranding the drug. Ultimately, though, it was the holding company, not Purdue Pharma, that was banned from doing business with public health programs, a Giuliani-arranged deal that allowed OxyContin sales to continue growing—and the epidemic to continue festering, largely unchecked.

Another factor to remember in the pursuit of Sackler and others to bring their buprenorphine wafer to market is the anecdotal reports of individuals withdrawing from buprenorphine. Regularly in my years of experience working with opioid addicts, those who used and/or abused buprenorphine reported how buprenorphine was harder for them to “kick” than heroin, methadone or any other opioid. Could we be looking at the creation of an entire population of individuals who are physically dependent on buprenorphine without the ability to discontinue the drug once they use it for an extended time period? See Pain Killers or the Politico article, “They Were All Lawyered Up and Rudy Giuliani’d Up” for more on how Giuliani fought for Purdue. Politico also unpacks some of the back-story to the 2007 plea agreement reached with Purdue by the DOJ.

10/23/18

Feuding Ideologies, Part 3

“Dying To Be Free,” an article on the opioid addiction crisis, was well written and effectively communicated its message. That message was that abstinence-based treatment “didn’t work well for opioid addicts.” Medication-assisted treatment (MAT), especially with Suboxone, should be the standard of care. Nominated for a Pulitzer, “Dying To Be Free” was said to have influenced “a series of state and federal policy changes” away from abstinence to embrace MAT. But it has a glaring blind spot with regard to MAT, particularly Suboxone.

Pragmatically speaking, abstinent-based treatment and MAT need to learn to work together in order to effectively address the opioid addiction crisis in the U.S. “Dying To Be Free” systematically put these two approaches as being at odds with each other. It suggested we need to choose between the two, and argued that we should choose MAT. In order to support Suboxone MAT, it failed to acknowledge several serious concerns with Suboxone and other MATs. In this sense the persuasive rhetoric of the article had a blind spot.

In what follows, I hope to shine a light on what was missed with regard to Suboxone and other MATs. My intent is to bring to light the potential cons with Suboxone treatment in order to counterbalance the many pros found in “Dying To Be Free.” In order to make a truly informed addiction treatment choice both the strengths and weaknesses, the pros and cons, need to be known and understood.

On September 20, 2017, Scott Gottlieb, the FDA Commissioner released a statement that said combined with counseling and behavioral therapies, MAT (medication-assisted treatment) was one of the main pillars of the federal response to the opioid epidemic. According to the Substance Abuse and Mental Health Services Administration (SAMHSA), it cuts the risk of death from all causes in half among individuals who use MAT to treat their opioid use disorder. But methadone and buprenorphine are themselves opioids and when they are combined with benzodiazepines or other central nervous system (CNS) depressants, there is a risk of serious side effects, such as difficulty breathing, coma and death.

Since the harm caused by untreated opioid addiction can outweigh these risks, the FDA advised against withholding buprenorphine or methadone-based MAT from individuals taking benzodiazepines or other CNS drugs. Nevertheless, the agency is requiring changes to the MAT drug labels to help decrease the risks of combining these drugs. Heath care professionals should educate patients about the risks of combined use, “including overdose and death.” They should taper the benzodiazepine or CNS depressant to discontinuation, if possible. They should verify the diagnosis if a patient was prescribed these drugs for anxiety or insomnia, and consider other treatment options for these conditions.

The new labeling recommends that health care providers develop a treatment plan that closely monitors any concomitant use of these drugs, and carefully taper the use of benzodiazepines, while considering other treatment options to address mental health conditions that the benzodiazepines might have been initially prescribed to address.

The FDA prescribing information for buprenorphine already notes that: “significant respiratory depression and death has occurred in association with buprenorphine,” particularly when it is used intravenously (IV) or in combination benzodiazepines or other CNS depressants, including alcohol. “Many, but not all post-marketing reports regarding coma and death associated with the concomitant use of buprenorphine and benzodiazepines involved misuse by self-injection.” Unintentional exposure of buprenorphine to children, which can cause possibly fatal respiratory depression, was warned against. It also notes the potential for dependence:

Buprenorphine is a partial agonist at the mu-opioid receptor and chronic administration produces physical dependence of the opioid type, characterized by withdrawal signs and symptoms upon abrupt discontinuation or rapid taper. The withdrawal syndrome is typically milder than seen with full agonists and may be delayed in onset. Buprenorphine can be abused in a manner similar to other opioids. This should be considered when prescribing or dispensing buprenorphine in situations when the clinician is concerned about an increased risk of misuse, abuse, or diversion.

Buprenorphine and methadone are both opioids, with the potential for physical dependence. Therefore, they are both diverted from legitimate medical treatment for illicit use. Buprenorphine is a Schedule III controlled substance, while methadone is a Schedule II controlled substance. Buprenorphine is said to have a tolerance ceiling with respiratory depression, meaning it has a lower potential when used alone to cause respiratory depression and death. Given that buprenorphine is a partial agonist, its physical euphoria is less intense than other opioids. But tolerance to many of the effects will develop with prolonged and repeated use.

Methadone was first synthesized by the Nazis, who never brought it into widespread use because of side effects, which included its addictive potential. After WWII, the Americans took control of the factory where methadone, then known as dolophine or polamidon, had been invented. A 1947 study demonstrated its addictive potential, warning if the manufacture and use was not controlled, “addiction to it could become a serious health problem.” See “The Consequences of Ignoring the Past,” for more on methadone.

The addictive potential and the abuse potential for buprenorphine or methadone was not readily discussed in “Dying To Be Free.” Nor were the above-noted concerns of mixing buprenorphine and CNS depressants. The author, Jason Cherkis, did say that neither drug was a miracle cure. “Suboxone blocks both the effects of heroin withdrawal and an addict’s craving and, if used properly, does it without causing intoxication.” But saying both drugs were comparable to “the insulin that a diabetic needs to live” was inaccurate and disingenuous. Chronic, long term use could lead to a lifelong dependency.

There is no getting around this. Chronic, long term use of buprenorphine and methadone produces physical dependence. A too rapid taper or an abrupt discontinuation will produce symptoms of withdrawal. Extended, chronic use over months or years could result in a lifelong reliance on the medication to avoid the discontinuation or withdrawal crisis—and the danger of returning to active illicit opioid use. In the documentary Methadonia, about methadone maintenance in New York City, one individual referred to methadone as “liquid handcuffs.”

Another disturbing blind spot in Dying To Be Free” was its discussion of a 2009 study, “Illicit Use of Buprenorphine/Naloxone Among Injecting and Noninjecting Opioid Users.” Cherkis cited it, stating the majority of addicts surveyed were buying Suboxone on the black market “in an attempt to get sober.” 74% of those surveyed said they were using Suboxone to “ease withdrawal symptoms; 64% said they were using it because they couldn’t afford drug treatment. “Even when purchased on the black market, regardless of the intentions of the user, the medication works as intended — as harm reduction.”

The study abstract contains the information Cherkis noted. But let’s take a closer look at the further results reported in the full article. First recognize the sample size was small: 51 injection opioid drug users (IDUs) and 49 noninjection opioid dug users (non-IDUs). It was also drawn from a limited area, opioid users in Providence, RI. Only 7% reported current employment and 52% reported current homelessness. The 64% who were using diverted Suboxone because they couldn’t afford treatment can be partially attributed to the high unemployment and homelessness figures.

In addition to the results reported by Cherkis was the following data. Among those who had used diverted buprenorphine, 60% reported using it for less than 1 week; 13% for 1 week; and 28% for more than 1 week. Of those using diverted buprenorphine less than 1 week, 32% said they only used it for one day. Fifty-seven percent said they used diverted buprenorphine because they couldn’t obtain heroin; a greater percentage (68%) of IDUs than non-IDUs (41%). Forty-seven percent said they used diverted buprenorphine to ‘get high’; a greater percentage of non-IDUs (69%) than IDUs (32%). Seventy-six percent said it was easy or very easy to obtain Suboxone on the street.

The following quote by Tom Frieden, the former director of the Centers for Disease Control and Prevention (CDC), appeared after the selective reporting on the above study, arguing for the need of more MAT programs: “If buprenorphine is being used and being bought on the street to self-treat addiction, that’s a reflection of a need to have better medically assisted treatment programs out there.”

I don’t really think these patterns of and reasons for diverted buprenorphine use are best described as harm reduction, as Cherkis said. Technically, there are high percentages of individuals saying they used it to reduce withdrawal, and/or self-treat opioid addiction, as well to stay “clean” for some time. But most also said they used buprenorphine because they couldn’t obtain heroin. The reported time of buprenorphine use for the majority of individuals was less than a week; 32% said it was for only one day! In addition, 32% of IDUs and 69% of non-IDUs said they used it to “get high.” It seems it would be more accurate to describe this behavior as attempting a time period of controlled opioid use, rather than a method of harm reduction aimed at curtailing opioid abuse or dependence.

About fourteen months before “Dying To Be Free” was published, “Addiction Treatment With A Dark Side” appeared in The New York Times. It too looked at Suboxone treatment, but presented a different, more nuanced side to Suboxone treatment. Cherkis selected out one aspect of the article, that it “linked hundreds of deaths in the U.S. to buprenorphine and Suboxone.” He focused in on the phrase used to say buprenorphine was a “primary suspect” as a cause of death in CDC data analyzed by the NYT. He then noted caution should be used before attributing a “primary suspect” drug as a cause of death, but neglected to show that is exactly what the NYT article did do.

The NYT article said the 420 deaths with buprenorphine as a “primary suspect” paled in comparison to those reported to the FDA from methadone for the same time period. It also said “The F.D.A. information, which is spare, does show that more than half of the American buprenorphine deaths involved other substances and that only two of 224 cases specifying ‘route of administration’ indicated injection — the primary concern of regulators.” Fifty deaths were noted as suicides, 69 as unintentional overdoses from drug abuse, and 30 were fetal or infant deaths after exposure in the womb.

The NYT claimed some experts believe buprenorphine is not being monitored systematically enough to gauge the full scope of its misuse. The CDC does not track buprenorphine deaths. Most medical examiners, emergency rooms, prisons, jail and drug courts don’t routinely test for it. The director of the Center for Substance Abuse Research at the University of Maryland said: “I’ve been studying the emergence of potential drug problems in this country for over 30 years. . . . This is the first drug that nobody seems to want to know about as a potential problem.”

Then “Addiction Treatment With A Dark Side” had a section noting some of the aggressive actions taken by Reckitt Benckiser, the company that brought Suboxone to market, “to protect its lucrative franchise.” I’ve noted these and similar actions by Reckitt Benckiser in previous articles: “A Double-Edged Drug,” “The Seduction of Opioid Substitution” and “The Opioid Buzzard.” The Times article documented the association between Reckitt Benckiser and the federal government in bringing Suboxone to market, and in providing a place for lucrative employment when government officials left public service for employment in the private sector.

At one point in “Dying To Be Free,” Cherkis said the “squeeze of regulation” was responsible for opportunistic forces, such as “cash only Suboxone clinics and shady doctors,” as well as the “vibrant black market for illicit buprenorphine. Read the section, “Troubled Histories” in the NYT article and the follow up NYT article, “At Clinics, Tumultuous Lives and Turbulent Care” to get a clearer, more accurate picture of the problems with some of the existing Suboxone treatment centers and providers.

You also find a lengthy section describing the benefits of Suboxone treatment. Cherkis did say in “Dying to Be Free” that the NYT article did not question the efficacy of Suboxone when it was used properly. But why didn’t he discuss or cite some of the concerns? I think it was because “Dying To Be Free” was intended to be a persuasive piece of rhetoric to promote the widespread use of buprenorphine in MAT.

Undoubtedly, “Dying To Be Free” has had a significant influence on opioid treatment. But it seems that it did not present a well-rounded picture of both the problems and the benefits with MAT, specifically Suboxone. It seems to have a biomedical bias with regard to conceiving and treating opioid addiction. In Part 1 of “Feuding Ideologies,” I indicated how its rhetoric was a straw man attack on abstinent-based treatment while it extolled MAT. In Part 2, I showed how it misrepresented the recovery philosophy of Alcoholics Anonymous. Here in Part 3, I looked at how its biomedical bias seemed to dismiss or ignore many of the problems with Suboxone as a MAT for opioid addiction.

01/23/18

Opioid Epidemic Price Gouging

The FDA recently approved Sublocade, the first once-monthly buprenorphine injection in its fight against the opioid epidemic. Indivior, the company which also sells Suboxone film, projected it would be available on the market sometime in the first quarter of 2018. Sublocade is a drug-device combination product. “It is injected by a healthcare professional (HCP) under the skin as a solution, and the delivery system form a solid deposit, or depot, containing buprenorphine.” The initial procedure will to be to start with daily stabilizing doses of Suboxone for at least seven days before the first injection of Sublocade.

After initial formation of the depot, buprenorphine is released by the breakdown (biodegradation) of the depot. In clinical trials, Sublocade provided sustained therapeutic plasma levels of buprenorphine over the one-month dosing interval.

Prescribing information for Sublocade said the recommended protocol was two monthly doses of 300 mg followed by 100 mg monthly maintenance doses. “Increasing the maintenance dose to 300 mg monthly may be considered for patients for whom the benefits outweigh the risks.” Sublocade will come in prefilled syringes of 100 mg and 300 mg. It will carry a boxed warning of the risk of serious harm or death if used intravenously.

The Indivior announcement of Sublocade’s approval indicated Sublocade will be distributed through a restricted distribution system, “which is intended to prevent the direct distribution to a patient.” This restricted release to only healthcare professionals is because of the risk of serious harm or death if someone were to attempt intravenous self-administration of Sublocade. Intriguingly, the boxed warning in the prescribing information wasn’t as clear on the intent of the restricted distribution system to prevent patients from having direct access to Sublocade. The harder it is to get a hold of Sublocade, the harder it will be to figure out a way to hack into the buprenorphine it contains.

The FDA is requiring postmarketing studies to assess four things. First, whether patients would benefit from a higher dose. Second, whether Sublocade can be safely started without a dose stabilization period of Suboxone. Third, to assess the feasibility of administering Sublocade at a longer inter-dose interval than once-monthly. Fourth, to determine a process for transitioning patients stabilized long term on Suboxone film to a monthly dose of Sublocade without the loaded dose in the first two months of treatment.

I assume the study to see if patients would benefit from a higher dose fits into the above prescribing information that maintenance doses could be increased up to 300 mg monthly. But I have this nagging question of whether Indivior felt unsure about the safety risk of maintenance doses above 100 mg. So they wanted to be safe rather than sorry, knowing there was always Suboxone film to supplement Sublocade in a pinch. And postmarketing studies could look at whether higher maintenance doses put people at risk in some way.

The procedure of having an initial “dose stabilization” period on Suboxone before injecting Sublocade helps ensure the individual has really stopped using opioids before their injection. The required postmarketing study will help evaluate whether that’s necessary. My initial thoughts are that given the significant amount of buprenorphine in the depot, clinically the dose stabilization period should remain, especially if this is done when the person is an outpatient. If the person’s pattern of use isn’t stable enough to reach a week of daily Suboxone use, they should probably try inpatient drug treatment to stabilize first before Sublocade.

Depots containing either 100 mg or 300 mg have a significant amount of buprenorphine. So I’m concerned about thoughts of assessing the feasibility of administering Sublocade at longer inter-dose intervals, which would require even higher doses. I guess the thinking behind the longer inter-dose interval study is anticipating of having/keeping Sublocade patients on the treatment for an indeterminate length of time, perhaps years.

Except for the supposed convenience of a once-monthly shot, why would someone who is stable on Suboxone film long term want to switch to Sublocade? If you have demonstrated the discipline, stability and willingness to successfully maintain opioid abstinence with Suboxone, why switch to Sublocade? I do know why Indivior would want you to switch. The average monthly cost for Suboxone is $132, while the average monthly cost for Sublocade is $1,580. The cost for Sublocade puts it in the ballpark for Vivitrol, which costs around $1,687 per month.

STAT News quoted one addiction professional who said: “It’s potentially a game changer. . . . This could become first-line [medication] for opioid addiction.” But Sublocade is just the first injectable buprenorphine product to be approved. A similar medication, known as CAM 2038, is made by Braeburn Pharmaceuticals and it could be get FDA approval by January 19, 2018. The president and CEO of Braeburn said: “This new technology has the potential to greatly influence the way patients are treated today. . . [It can] free patients from the daily decision and reminder of the disease.” Did this guy ignore or just forget about the Warnings and Precautions on the Sublocade medication guide?

It says: “Buprenorphine can be abused in a manner similar to other opioids; Warn patients of the potential danger of self-administration of benzodiazepines or other CNS depressants while under treatment with Sublocade.” Pain treatment should be with a non-opioid analgesic whenever possible. “If opioid therapy is required, monitor patients closely because higher doses may be required for analgesic effect.” Sublocade won’t free patients of the daily reminder of the disease, because it is the daily reminder.

STAT said long-acting buprenorphine could make future inroads within the criminal justice system. “In recent years judges, wardens, and health officials have warmed up to Vivitrol, citing fears that daily tablets of buprenorphine can be diverted or abused.” Additionally, the criminal justice system has been more receptive to Vivitrol because Alkermes has been doing targeted marketing with them to promote Vivitrol for a number of years. However, the approval of Sublocade adds a second monthly injectable alongside Vivitrol and potentially could diminish “one of the biggest competitive advantages held by Vivitrol.”

STAT also pointed to another likely financial incentive for Invidior to put Sublocade into the market. Medicaid spending on buprenorphine last year was five times higher than for Vivtrol. But those spending statistics could be partly due to the cost discrepancy between monthly Vivitrol and Suboxone and not the preference for buprenorphine. However, it is likely Invidior will be able to slice off a nice chunk of non-negotiated drug price income for Sublocade from Medicaid.

Another STAT article discussed a study published in The Lancet, Lee et al., that found both Vivitrol and Suboxone had comparable effectiveness outcomes during 24 weeks of outpatient treatment. STAT quoted Dr. Nora Volkow, director of NIDA as saying she hoped the study will change the widespread prejudice patients don’t do as well on naltrexone as they do on buprenorphine. Apparently it didn’t. In the very same STAT article, two different doctors, not involved in the study, said the study showed buprenorphine was more effective than Vivitrol. However, the lead author of the study, Dr. Joshua Lee told STAT: “Both medications worked quite similarly and, therefore, both should be discussed as treatment options.”

The study findings pointed to by the two doctors included the following: its easier to initiate and patients stay with the treatment (buprenorphine) longer. Fewer participants successfully started Vivitrol treatment, as it required a three day period for detoxification, whereas Suboxone participants could begin as soon as the onset of withdrawal symptoms began. The differences in induction rates were 72% for Vivitrol and 94% for Suboxone.

Naltrexone (Vivitrol) is an antagonist, meaning if there were residual levels of opioids in a participant’s body they would immediately be thrown into acute withdrawal. The delay was medically necessary. Naltrexone is also not an opioid, while Suboxone (buprenorphine) is. The induction period with Vivitrol was expected by the study authors themselves to be more difficult. They didn’t get the easement of acute opioid withdrawal that the Suboxone group did—and yet, 72% were successfully inducted into the study.

Curiously one individual pointed to where many of the overdoses in the study occurred after detox, apparently indicating more occurred with Vivitrol. Yet she failed to comment on the fact that of the five fatal overdoses in the study, THREE were in the Suboxone group!

There were more relapse events (defined as 4 consecutive weeks of any non-study opioid use by urine toxicology or self-report, or 7 consecutive days of self-reported use.) for the Vivitrol group, but “most or all of this difference [was] accounted for by early relapse in nearly all (70 [89%] of 79) XR-NTX induction failures.” The more difficult time intiating patients into Vivitrol treatment effected the over relapse rates. “However, once initiated, both medications were equally safe and effective.”

The Lee et al. study was actually the second study to demonstrate that Vivitrol was as effective as Suboxone in maintaining short-term abstinence. The previous study was a smaller Norwegian study, Tanum et al., that followed its participants for 12 weeks. The bottom line is replicated results are more difficult to rationalize away.

Diversion and abuse of Suboxone has been evident from the time it was approved by the FDA. The approval of Sublocade would hopefully nullify the diversion and abuse problems experienced with Suboxone, if you have the money or insurance for it.

Bringing buprenorphine into the realm of “a restricted delivery system” to prevent direct distribution to patients also seems to be where some justification for the added cost factor comes in. But I wonder to what extent dispensing Vivitrol and Sublocade in a medical setting can justify the high cost. Is there price gouging going on? This is now the second time that technological innovation has extended patent exclusivity for Indivior’s buprenorphine products. Read more about how Reckitt Benckiser, the parent company to Indivior and Indivior itself accomplished this in “The Opioid Buzzard.”

Faith Seeking Understanding

Charles Sigler, D.Phil.

Tag Archives: buprenorphine