Tag: Reckitt Benckiser

12/3/19

The Pied Pipers of Suboxone

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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 9th 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 15th, 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 19th, 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 20th. Mylan, which had made a deal with Indivior, announced it will launch its generic version on February 22nd.

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.”

12/20/16

The Opioid Buzzard

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The U.S. is in the midst of a health crisis from the use and abuse of opioids. Since 1999, the rate of overdose deaths from opioids—prescription pain relievers and heroin—nearly quadrupled. On an average day in the U.S. more than 650,000 opioid prescriptions are dispensed; 3,900 people begin nonmedical use of opioids; 580 people start using heroin; and 78 people die from an opioid-related overdose. Economically, there is a $20 billion cost in emergency department and inpatient care for opioid poisoning each year; and $55 billion spent on health and social costs related to prescription opioid abuse.

In order to address this opioid epidemic, the U.S. Department of Health and Human Services (HHS) launched an initiative in March of 2015 aimed at improving prescribing practices, expanding the access to and use of medication-assisted treatment and expanding the use of naloxone. So far, the Substance Abuse and Mental Health administration (SAMHSA) has awarded $10.7 million to 11 high-burden states for medication-assisted treatment (MAT). Applications were due in May of 2016 and awards were to be made to an additional 11 states. The above information and statistics were drawn from a Health and Human Services report, “The Opioid Epidemic: By the Numbers.”

Then in July of 2016, the HHS Secretary announced new rules that permit doctors licensed to dispense buprenorphine to see as many as 274 patients per year. The old limit was 100. HHS estimated that change permits as many as 70,000 more people to access buprenorphine. The former limit of 100 was seen by many as a barrier to individuals seeking to access MAT. “The rule aims to increase access to medication-assisted treatment and associated behavioral health supports for tens of thousands of people with opioid use disorders, while preventing diversion.” Clearly buprenorphine products like Suboxone are seen as a crucial element in our attempts to combat the opioid health crisis.

There are issues with this approach to treatment for the opioid crisis that I’ve addressed previously in articles such as: “The Seduction of Opioid Substitution” and “A Double-Edged Drug.” Here I want to look at how the company that brought buprenorphine treatment to market, Indivior/Reckitt Benckiser, tried to position itself as the primary service provider for buprenorphine-based MAT in the U.S. It’s kind of like a buzzard chasing off smaller scavengers from the carcass of an overdose victim. At one point, Reckitt Benckiser had 85% of the U.S. MAT market—almost all of it subsidized by taxpayers.

In 1994 Reckitt Benckiser established the Buprenorphine Business Group to develop buprenorphine as a treatment for opioid dependence. In 2000 legislation (DATA 2000) was passed in the U.S. permitting office-based treatment of opioid dependence. In 2002 the FDA approved Subutex (buprenorphine) and Suboxone (buprenorphine and naloxone) for the treatment of opioid dependence in the U.S. These products came to market in 2003. In 2007 the initial cap of 30 patients was raised to 100 for physicians with at least one year’s experience with buprenorphine. That same year Reckitt Benckiser acquired the rights for the sublingual film version of Suboxone from MonoSol Rx. Then in 2010 Suboxone sublingual film was launched in the U.S. Subutex tablets were discontinued in 2011; and Suboxone tablets met the same fate in 2012. In December of 2014, Reckitt Benckiser spun its specialty pharmaceutical company into a separate business and Indivior was born.

This history was taken directly from the Indivior website, where the company estimated they had treated 5 million individuals in the U.S. with Suboxone film and tablets and Subutex tablets. Here are some additional facts to add to the above timeline from a 2013 article, “Pharma Gamemanship.”

Reckitt Benckiser (RB) knew it only had patent exclusivity for their buprenorphine products until 2009. But they had a plan to circumvent the pending loss. As noted above, they acquired the rights for the sublingual film version of Suboxone in 2008. In October of 2008 they submitted a New Drug Application to the FDA for the film version of Suboxone; and it was approved in August of 2010. Reckitt Benckiser has patent exclusivity on the newer film version until 2023.

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. Reporting for The Daily Beast, Christopher Moraff said the “data” they based their withdrawal of Suboxone tablets on was a single study RB had paid for itself. RB reportedly said the study demonstrated the risk factor for accidental ingestion was eight times higher in bottled tablets than for the individually packaged film. Yet its own data told a different story.

Compared to the more than 20,000 deaths in 2012 from prescription opiates and heroin, pediatric poisoning from Suboxone was far from a public health crisis. A preliminary study commissioned by Reckitt Benckiser found just 46 cases of serious injury or death out of more than 2,200 accidental pediatric exposures to Suboxone tablets between 2010 and 2012—which researchers described as not significantly different from poisonings from the film.

The FDA thought the RB study was inconclusive and did not demonstrate any difference in the safety profile or abuse potential of the two formulations. They said the study was poorly designed and conducted. “Reckitt’s own actions also undermine, to some extent, its claims with respect to the severity of this safety issue.” Despite the first report of pediatric death in June of 2010, RB continued marketing the tablets in multi-dose containers for two more years. And it continues to sell them throughout Europe, where Suboxone tablets are still under patent.

In June 2013 the FTC opened an investigation into whether Reckitt Benckiser abused public regulatory processes and fought for nearly two years to obtain more than 20,000 documents the company was fighting to withhold. That case is ongoing. In December of that year, federal agents raided Reckitt Benckiser’s West Virginia offices after the Department of Justice launched a criminal probe into the company’s Suboxone business. That investigation continues.

Public Citizen said that few, if any, companies went as far as RB to pre-emptively withdraw an off-patent drug from the market to make room for a newly patented successor. 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.

So it should come as no surprise that a lawsuit has been filed by 35 states and the District of Columbia alleging that Indivior violated antitrust laws by trying to extend its monopoly over Suboxone. Reporting for CNN, Susan Scutti said the lawsuit charges that Indivior/RB and MonoSol Rx “conspired to block generic competitors for Suboxone by switching the drug from a tablet to a dissolving film.” A September 23, 2016 press release on the Indivior website said: “The Company intends to continue to vigorously defend its position.”

The International-Dictionary.com said there are two meanings for the word “buzzard.” The first one is zoological, referring to a bird of prey of the hawk family. The second meaning is “a blockhead; a dunce.” A quote attributed to Goldsmith reads: “It is common, to a proverb, to call one who can not be taught, or who continues obstinately ignorant, a buzzard.” It seems to me that either sense can be applied to Reckitt Benckiser and Indivior.

02/12/16

A Double-Edged Drug

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© arkela | 123f.com

Dee Roberts referred to Suboxone (buprenorphine) maintenance as “withdrawal avoidance” while describing her journey from Vicodin to Suboxone to tapering off of Suboxone. The truth of the statement stung. She said she developed a “deeply rooted” fear of not having the medication with her. Does that sound familiar? Tellingly she said: “My behavior on Suboxone and while using had some alarming similarities.”

In “Kicking Suboxone: The Last Milligram” she described her efforts to break free from what had initially promised her freedom from the Vicodin-vodka cocktail that had stopped working for her. She said she was one of the first to try Suboxone when it became available in 2003. But “not one doctor who saw me suggested I consider going off of the drug. I stayed on it for 10 years until the side effects added up, motivating me to make the final jump.” She spent over $50,000 dollars out of pocket on doctor’s visits and drug co-pays.

If it weren’t for an adrenal imbalance that developed, she thinks she might well have continued taking it for many more years. But that wasn’t her only adverse effect. After a couple of years, she noticed personality changes. She felt like she was watching someone else’s story unfold. She wasn’t able to put words to the experience at the time. “The fighter in me had retired without notice.” She developed a skewed appetite, going from sugar fix to sugar fix. The final straw was when she noticed her hair falling out.

She tried several consultations before she found a doctor willing to help her taper off of buprenorphine (Suboxone). “As if waving a voodoo doll, I was warned multiple times about tempting relapse.” It had been 11 years since her last illicit prescription. She said she found it difficult to separate real withdrawal symptoms from psychosomatic ones in her tapering process. I’d suggest that a better distinction would be between acute withdrawal symptoms (her sense of “real” withdrawal symptoms) and post acute withdrawal symptoms (what she called psychosomatic ones).

Dee’s journey is described in more detail in her original article for The Fix. It involved off-and-on sleep deprivation, bouts of depression, stomach pains, hot and cold flashes, an emotional rollercoaster ride, and the help of a Border Collie mix who became her personal trainer. She had to find her own way out of her withdrawal avoidance disorder, “Since there have been no long-term use studies on Suboxone, side effects are often downplayed or ignored by the medical community.” She referenced a doctor in Boca Raton Florida, Steven Scanlon MD, who wrote a helpful article on “Detoxing from Suboxone.” He said:

 Patients, the first question you need to ask your current Suboxone doctor is whether he has ever taken anyone completely off Suboxone or Subutex.  If he says that he just tapers a patient down after they have been on it long-term and they are fine, then he is disingenuous or at least ill-informed.  If he tells you that he is going to put you on 16mg sublingually for six months while your brain stabilizes and heals and then taper you off it he is purposely or unknowingly misleading you.  How can your brain heal if you are still taking an extremely potent opioid that is classified as a pain medication and approved by the FDA as a medication to treat severe pain? On the other hand, if he tells you about the symptoms I discuss below and has previously helped people get off Suboxone when they are ready, then stick with this doctor and do what he says. When I detox patients off Suboxone I follow them for approximately 5 or 6 months and see them once a week during that time.  I make sure to follow them for at least two months after we stop the Subutex.  I do not use Suboxone, only Subutex, and I will explain why not.

Dawn Roberts suggested that to get a sense of the scope of the problem with recovering addicts who are desperate to get off of Suboxone, type “get off Suboxone” into a search engine. I found over 16,000 results. Then I tried “Suboxone taper” and had over 8,000 results. “Suboxone withdrawal tips” garnered 47,900 results. “Suboxone withdrawal help” had 184,000 hits; and “Suboxone withdrawal symptoms” had 410,000 hits. Writing for The Fix, Roberts investigated why there was no official protocol to detox addicts off Suboxone in “So You Thought You Could Get Off Suboxone?”

She provided a brief history of the process that Reckitt Benckiser Pharmaceuticals (RBP) used to bring Suboxone to market and turn it into a blockbuster drug. They spent ten years and millions of dollars to cultivate the buprenorphine formula and another 13 years to bring Suboxone to the market in 2002. They lobbied Congress to create the Drug Addiction and Treatment Act of 2002 (DATA). Then RBP worked with NIDA and the FDA to lay the foundation to introduce Suboxone to the market. Their efforts garnered RBP $1.23 billion in sales in 2011 and $1.35 billion in sales in 2012. According to RBP’s annual report, Suboxone sales were $1.2 billion in 2013, ranking it at #39 of the top 100 drugs prescribed in the US. Oh, and Genetic Engineering & Biotechnology News ranked Suboxone as the most abused drug of 2014.  Zubsolve, another buprenorphine/naloxone product, was ranked as the 12th most abused drug that same year. Note also that the DEA classifies these drugs as Schedule III controlled substances.

Roberts then related how Reckitt Benckiser told her they were not aware of an established guideline or protocol for titration (tapering) off of Suboxone. A RBP spokesperson said:

Patients seeking to discontinue treatment for opioid dependence should be advised to work closely with their healthcare provider on a tapering schedule and should be apprised of the potential to relapse to illicit drug use associated with discontinuation of opioid agonist/partial agonist medication-assisted treatment.

Roberts concluded that RBP outright refuses to study the long-term effects of buprenorphine maintenance. And it seemed that the company was intolerant of buprenorphine patients who decide they want to discontinue Suboxone substitution treatment. I’m beginning to hear a line from the Eagles song, “Hotel California” in my head: “You can check-out any time you like, but you can never leave.”

Guinevere, on Guinevere Gets Sober, a great recovery blog, came to the same conclusion.  In “Suboxone Detox Redux,” she noted that Tim Baxter, the global medical director for RBP, told her: ”We don’t promote detox” from Suboxone. She decided RBP wants you to stay on the drug. Guinevere also recommends Dr. Scanlon’s paper, “Detoxing from Suboxone.” Read her article for good advice if you are considering any attempt to taper or titrate off of buprenorphine.

It seems that RBP has been trying to build a clientele that will continue using their Suboxone products for extended periods of time. Here is an article describing in some detail the gamesmanship of RBP over the years that Suboxone was under patent. RBP lost their exclusivity rights to Suboxone in 2009. However, they submitted a New Drug Application to the FDA for a sublingual film version of Suboxone in October of 2008. It was approved in August of 2010 with patent exclusivity until 2023. In their 2011 annual report, RBP said that competition from generics could take up to 80% of the revenue and profit of the Suboxone tablet business in the US. But they expected “that the Suboxone film will help mitigate the impact.”

Then in September of 2012, RBP announced that they were voluntarily withdrawing the tablet form of Suboxone from the market, citing data they had received from the US Poison Control Centers indicating high rates of pediatric overdose on the tablet formulation. But they were manipulating the market by offering discounts on the sublingual film version while raising the price of the tablets. Hours after announcing their plan to take the tablets off the market, RBP announced they had filed a “citizen’s petition” urging the FDA to require all manufacturers of buprenorphine-containing products to implement safeguards to prevent pediatric exposure, etc. They also asked the FDA to reject any new drug applications for buprenorphine (generic Suboxone) tablets. The FDA didn’t bite and approved generic tablet versions of Suboxone. Janet Woodstock, the Director of the FDA Center for Drug Evaluation and Research, said:

The timing of Reckitt’s September 2012 announcement that it would discontinue marketing of the tablet product because of pediatric exposure issues, given its close alignment with the period in which generic competition for this product was expected to begin, cannot be ignored.

Writing for The New York Times, Deborah Sontang published two articles on the pros and cons of Suboxone: “Addiction Treatment With a Dark Side” and “At Clinics, Tumultuous Lives and Turbulent Care.” The doctor running a clinic near Pittsburgh was quoted as saying, “I know on the surface it might look like a pill mill. . . . We’re seeing a fair number of patients, and they’re primarily receiving a prescription.” But he added they encourage, support and don’t judge. “There’s a kind of love.” Read the article to get a clearer picture of his bedside manner. After his “recovery” and entrance into the Suboxone clinic business, Ohio revoked his medical license in 2011 because he had forged signatures verifying his attendance at 12-Step meetings. Pennsylvania suspended his license in 2010 for failing to submit to three unannounced drug tests while he was on vacation.

So getting on Suboxone maintenance is like checking into the Hotel California:

Last thing I remember, I was
Running for the door
I had to find the passage back
To the place I was before
“Relax, ” said the night man,
“We are programmed to receive.
You can check-out any time you like,
But you can never leave!

If you want to hear the entire Eagles song, listen here.

IRETA, the Institute for Research, Education & Training in Addiction, seemed to disparage Sontang’s portrayal of buprenorphine as a “double-edged” drug. They concluded their reflections with the following: “Singling out buprenorphine as ‘the’ double edged drug seems an inaccurate and potentially stigmatizing view of it.”  I’m not buying their rhetoric. From what I’ve seen, buprenorphine really IS a double-edged drug.

10/5/15

The End of Alcoholism? Part 3

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© f8grapher | 123rf.com

“One of the first duties of the physician is to educate the masses not to take medicine.” Sir William Osler, physician

Olivier Ameisen wrote in The End of My Addiction that thoughts about an addictive substance could insinuate themselves into an addict’s consciousness and quickly preoccupy the whole mind with anxiety about how to get it. “This is a harrowing experience mentally and emotionally as well as physically, because it is charges with shame and self-loathing for even experiencing the craving.” Cravings could propel him into a trance-like state. He would set out to buy liquor, feeling as if someone else was controlling his body. “When craving defeated me, I could only hope, pray, and strive to do a better job of resisting it the next day.”

Ameisen was “a French-American male physician with alcohol dependence and comorbid pre-existing anxiety disorder.”  He said he had been plagued by anxious feelings of inadequacy throughout his life. He’d been seeing therapists for a long time before he started drinking. They were never much help with his anxiety. “Nor was the Xanax they prescribed me.” So he turned to alcohol.

I was terrified of living without alcohol. Without it, I would be an anxious wreck. Admitting my problem drinking to most of my friends and my colleagues terrified me too. I feared being ostracized, and since I felt that drinking should be under my control I felt ostracism would be justified.

He told every physician and therapist he saw that his fundamental problem was anxiety, “which expressed itself in chronic muscle tension, and which intensifying to a panic state, triggered the overwhelming need to drink for relief.” None of the addiction professionals took him seriously. So he looked around to prescribe his own treatment. He thus disregarded another observation of the Canadian physician, William Osler: “A physician who treats himself has a fool for a patient.”

An old girlfriend sent him a copy of a New York Times article that discussed baclofen reduced craving with cocaine, but he was in the midst of a binge and misplaced the copy. He eventually contacted the doctor mentioned in the article and asked her about baclofen. Although he was encouraged by the conversation, his alcohol treatment specialist and psychiatrist weren’t interested in discussing an unproven medication. In early February of 2002 he began doing an internet research into baclofen. Panic was his most crippling symptom, so he searched first under “baclofen panic.” He found several reported studies, including the 2000 study by Addolorato, “Ability of baclofen in reducing alcohol craving and intake.”

Ameisen developed a theory that there is a “threshold dose” of baclofen needed to break the cycle of craving, preoccupation and obsessive thoughts with alcoholism. And he decided to try out the theory on himself. He began his self-medicated treatment with baclofen on January 9, 2004. See “The End of Alcoholism? Part 1” for a fuller description of this process. Ameisen did attempt social, controlled drinking, about fifteen months after establishing alcohol abstinence by taking baclofen. But he said he preferred not drinking. James Medd in The Guardian suggested that “He can now drink socially—an idea entirely counter to the teachings of AA and most other therapies.”

Ameisen saw anxiety as his primary disorder, with his drinking as a way to self-medicate his anxiety. Additionally, he held on to a belief that he should be able to control his drinking: “I should be able to control my urge to drink. . . . Since I felt that drinking should be under my control, I felt ostracism would be justified.” Even though he reportedly went to hundreds of Alcoholics Anonymous (A.A.) meetings, if he held onto a belief that he should be able to control his drinking, he would not be able to effectively use A.A. to remain abstinent, because he didn’t entirely accept their first Step: “We admitted that we were powerless over alcohol, and that out lives had become unmanageable.”

Other medical professionals were concerned with his use of high dose baclofen. Jonathan Crick, the psychiatrist who is the editor-in-chief of Alcohol and Alcoholism, said he’s been encouraged with his own treatment of 50 patients with baclofen, but won’t use the high doses of Ameisen’s method. He stays under 100 mg a day. “I do actually have some concerns about unwanted effects in large doses. . . . This is a drug which is active in the brain, and there are some concerns about some unwanted effects of higher doses.”

I also wonder if he turned a blind eye to some of the concerns raised about baclofen in the literature. He saw it as essential to his own ability to manage anxiety, cravings, and to refrain from compulsive, out of control drinking.

There have been a series of studies reporting what has been called a “baclofen withdrawal syndrome.” A 1981 article, Complication of Baclofen Withdrawal, reported that three patients taking baclofen on a long-term basis experienced hallucinogens and/or seizures with abrupt reduction of their dose or discontinuation of baclofen therapy. A 1998 article, “Prolonged Severe Withdrawal Symptoms,” reported that an abrupt decrease or too rapid taper off baclofen could result in a withdrawal syndrome manifesting hallucinations, delirium, seizures and high fever.

A 2005 study, “Delirium Associated with Baclofen Withdrawal,” reviewed 23 published cases of psychiatric symptoms with baclofen withdrawal. Delirium, but not other symptoms was found to arise from abrupt baclofen withdrawal. The delirium appeared to be greater in individuals who received chronic baclofen therapy. A 2001 case study reported on the case of a man with neuroleptic malignant-like syndrome, with disorientation, signs of autonomic dysfunction and rigidity from abruptly stopping his long-term baclofen treatment. “He improved markedly after the reintroduction of baclofen.”

In contrast to published studies saying that baclofen helped with alcohol withdrawal, a Cochrane review published in May of 2015, “Baclofen for alcohol withdrawal syndrome,” concluded that the evidence for recommending baclofen for alcohol withdrawal syndrome was insufficient. “We therefore need more well-designed RCTs to prove its efficacy and safety.”

A 2013 article assessed the potential to confuse baclofen withdrawal for alcohol withdrawal. The authors said the clinical and psychopharmacological overlap between acute intoxication and the withdrawal symptoms of baclofen, alcohol and benzodiazepines could lead to diagnostic uncertainty. “In every case of unexplained confusion, agitation, hallucinations, seizures, and psychosis occurring in patients with current drinking, both AWS and BWS should be systematically considered.”

A small study by Franchitto et al. in 2013 did a retrospective study of the medical records for 12 individuals diagnosed with alcohol dependence who had overdosed on baclofen. The median dose of ingested baclofen was estimated at 340 mg. Ten had a previous suicide attempt. Three had co-ingested benzodiazepines. The “classic” effects of baclofen overdose associated with neurotransmitter inhibitory effects were evident:

Impaired consciousness or coma, generalized muscular hypotonia with absent limb reflexes, respiratory depression, seizures, hemodynamic changes and cardiac abnormalities such as supraventricular tachycardias, premature atrial contractions and first-degree heart block.

Four patients were in coma before admission, and required intubation and respiratory support. Coma after a baclofen overdose may persist for several days because of the drugs’ depression of neuronal activity in the central nervous system. Nevertheless, the authors concluded that consistent with other reports, “most patients with baclofen overdose had a good outcome with adequate supportive care.”

There have been reports of heart problems and even mania. A 2014 case report concluded that cardiac arrest occurred with baclofen withdrawal syndrome. A 2014 article concluded that baclofen-induced manic symptoms could appear in individuals regardless of a history of bipolar or mood disorders. The question to be raised about the use of baclofen for alcohol use disorders is what effects does it have on the brain? To the extent that these effects correspond to the effects of alcohol, or any other potentially “addictive” substance, its use in substance misuse treatment is a double-edged sword.

A 2015 study by Rigal et al. reviewed the records of 146 patients who used baclofen to treat their alcohol use disorder. Ninety (78%) reported at least one adverse effect. The most frequently reported adverse effect was a disruption of the wake-sleep cycle in 73 patients (63%). “Persistent adverse effects occurred in 62 patients (53%).” There were 8 patients who had adverse effects that led them to stop taking baclofen. Women reported more adverse events than men. “High-dose baclofen exposes patients with alcohol disorders to many adverse effects. Generally persistent, some adverse effects appear at low doses and may be dangerous.”

The evidence seems clear for a baclofen withdrawal syndrome. There is a state of tolerance or dependence that develops with long term, high dose use. Are patients given baclofen informed of the potential for them to develop a dependency upon this medication? My concern is this dependency is a “sleeper” symptom that initially goes largely unnoticed as with medications used to “treat” opioid use disorders—buprenorphine, and methadone. This same problem with dependency also exists with benzodiazepines prescribed for anxiety or sleep disturbance. They initially work so effectively that the dependency, if it’s noticed at all, is minimized. Only after it becomes seriously entrenched physically and psychologically do people realize what has happened.

So where might all of this lead? Baclofen is a generic drug with no potential for a pharmaceutical company to patent, and thus become a highly profitable product for them. So pharmaceutical companies are largely not interested in developing baclofen as a treatment for addictions. However, there is a prodrug version of baclofen called arbaclofen palcarbil that was initially in development by XenoPort as a treatment for GERD and spasticity due to multiple sclerosis. In May of 2013, XenoPort announced that Phase 3 clinical trials for arbaclofen palcarbil were unsuccessful and they decided to terminate further investment in the program.

In May of 2014, Reckitt Benckiser Pharmaceuticals and XenoPort announced they had entered into a joint license agreement, where Reckitt Benckiser will have the exclusive rights to develop and commercialize arbaclofen palcarbil as a treatment for alcohol use disorder.ClinicalTrials.gov indicated that a Phase 2 study by Reckitt Benckiser was scheduled to begin in September of 2015 and should be completed by April of 2016. The purpose of this clinical trial is to determine the maximum tolerated dose of arbaclofen palcarbil in treating alcohol use disorder.

Reckitt Benckiser appears to be looking for a replacement blockbuster product since its opioid treatment drug, Suboxone, went generic. Before losing its patent rights, Suboxone had become a billion dollar drug for Reckitt Benckiser, rising to the 25th best selling drug of 2010, according to drugs.com. The existing research on baclofen gives us a pretty good idea on what the future holds for any arbaclofen palcarbil product. Also, the potential population for a maintenance drug for alcohol use disorder is significantly larger than there was for an opioid maintenance drug. If Reckitt Benckiser can successfully move arbaclofen palcarbil through the FDA approval gauntlet, we will see a patented knock off product of baclofen on the market to treat alcohol use disorder in a few years.

Suboxone made another top drug list in 2013. It was listed as the #2 most abused prescription drug of 2013 by Genetic Engineering & Biotechnology News. Hopefully, any arbaclofen palcarbil product will not repeat that ‘achievement’ for Reckitt Benckiser.