12/30/16

The “Hotel California” Effect

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Alkermes is a believer in the classic idiom, the third time’s the charm. The pharma company recently announced success on its third-late stage clinical for ALKS 5461, which it hopes will become a new antidepressant blockbuster. In January of 2016 two previous phase III trials failed to achieve their primary endpoints and the company’s stock price took a nosedive. After the positive results of the FORWARD-5 study, shares were up over 30%. Alkermes plans to meet with the FDA in order to argue that despite failing in its two previous phase III clinical trials, the FDA should approve ALKS 5461 and “bring this new medication to patients with MDD [major depressive disorder].”  FDA regulations require a total of two successful phase III trials with statistical significance over placebo. What’s going on here?

The FORWARD-4 clinical trial tested two dose levels of ALKS 5461, 2mg and .5 mg and it failed to meet its initial primary endpoint, “change from baseline in the Montgomery Asberg Depression Rating Scale (MADRS) total score.” Post-hoc statistical analysis done on the FORWARD-4 data indicated the group receiving the higher 2mg dose of ALKS 5461 had a statistically significant difference on the MADRS. Alkermes then decided to “update” their methodology and analysis for FORWARD-5. In other words, Alkermes used statistical analysis of the failed FORWARD-4 trial to uncover a significant result within a subpopulation of the study that was not targeted in their initial study design. They then modified their methodology and analysis of the FORWARD-5 trial to match the post-hoc analysis.

In a previous article on the FORWARD-3 and FORWARD-4 failed clinical trials, “Nearsighted Drug Development,” I expressed the opinion that this seemed a bit like cheating. Nevertheless, it seems that changing the methodology from what was initially proposed for an ongoing trial is permitted. But would it be appropriate for the FDA to reconsider the post-hoc analysis of the FORWARD-4 trial as a “successful” clinical trial? It seems a bit like trying to argue that the FDA should give Alkermes credit for positive results in FORWARD-4 even though those positive results only became apparent after the fact—when they began to fiddle around with the data to see if they could find something positive.

Another disturbing claim by Alkermes is with how they describe ALKS 5461. It is “designed to rebalance brain function that is dysregulated in the state of depression.” As I pointed out in “Nearsighted Drug Development,” the chemical imbalance theory of depression is now said to be an urban myth even by pro drug psychiatrists like Ronald Pies.

If approved, ALKS 5461 is proposed as an add-on, adjunctive medication in the treatment of major depression for patients “with an inadequate response to standard antidepressant therapies.” However, there is a hint that if approved ALKS 5461 could be put forward by the company as a standalone treatment for depression. Elliot Ehrich, the CMO of Alkermes, said the studies in the FORWARD program contributed data useful in assessing the safety and efficacy of ALKS 5461 on a standalone basis and if taken as an adjunct medication.

It also appears that if the FDA does not agree to approve ALKS 5461 as a treatment for MDD based upon the above discussed rationale, Alkermes will drop it. Richard Pops, the chairman of Alkermes, said they are not planning to conduct any additional studies on ALKS 5461. Is this just a cut your losses decision to forego the additional cost of another clinical trial for the company? Or is it a veiled threat to the FDA that Alkermes will shelve any future work on a product that was once approved by the agency for a fast track drug development status? In other words will the FDA permit post hoc analysis of a phase III clinical trial turn a failed trial into a successful one?

What is at stake here is that the active ingredient in ALKS 5461 is a known opioid, with an acknowledged addictive potential—buprenorphine. Buprenorphine is a Schedule III controlled substance.  Combining it with an opioid antagonist (samidorphan) does not lessen its addictive potential. In higher doses buprenorphine is used as a maintenance drug therapy for opioid dependence (Suboxone; Subutex; Zubsolv). Regularly, opioid dependent individuals have told me that getting off of buprenorphine was harder than heroin or methadone.

Higher doses and longer term use of buprenorphine influence the length of time for withdrawal or discontinuation. And guess what, depression is one of the commonly experienced withdrawal symptoms. The Addiction Blog posted some helpful information on “How long does buprenorphine withdrawal last?” Note that the website is not taking an anti-buprenorphine position. It begins by saying “Buprenorphine can be a useful drug prescribed to treat opiate addiction.”

Within the first 24 to 72 hours, physical withdrawal symptoms peak in severity and intensity with common symptoms such as: diarrhea, sweating, nausea, dilated pupils, watery eyes and restlessness. As the first week progresses, aches, stomach cramps, and joint pain will probably continue. General feelings of discomfort and problems sleeping can occur. “Mood swings are also common, with bouts of anxiety or depression.”  After two weeks, the pain and discomfort of acute physical withdrawal should be less severe, but depression and an extreme loss of motivation can set in.

After [the] three to four week mark, most of the physical withdrawal symptoms will be gone, however … intense drug cravings may be present for those addicted to buprenorphine. Depression is also common. This time is very important, as you will be very vulnerable to relapse. . . . However, psychological withdrawal symptoms can last for months after cessation.

Now “relapse” here refers to resuming active opioid use or abuse. But in reviewing the withdrawal symptoms described above, the relapse experienced could just as easily be interpreted as a depression relapse by individuals attempting to taper off of long term ALKS 5461 use.

So someone could add ALKS 5461 to their antidepressant of choice, take it for an extended period of time and see a clear remission of their depressive symptoms. If they were to then attempt a taper off of ALKS 5461, they would likely experience the above described buprenorphine withdrawal symptoms, interpret them as a return of depressive symptoms, and resume using ALKS 5461. If ALKS 5461 is used as a stand-alone treatment for depression, a misinterpretation of withdrawal symptoms as a relapse of depression is also likely occur. Similar to long-term antidepressant users, there could be a “Hotel California” effect—you can taper down any time you want, but you can never leave.

With continued use of buprenorphine, there comes a point where the brain produces an inadequate amount of neurotransmitters in the body. People going through buprenorphine PAWS [post acute withdrawal syndrome] manifest long lasting changes in the brain as a result of long term use. These changes are slower to reverse and can persist for many months, depending on the frequency and amount of past dosing.

I don’t know whether the above concerns will be considered in an FDA review of the Alkermes request to approve ALKS 5461. I hope they are. But if Alkermes is successful in bringing its drug to market, “where new therapeutic options are highly sought after as millions of patients in the U.S. do not respond to standard courses of antidepressant therapy,” be prepared for what seems to be an unavoidable cycle of depression treatment perpetuating depression and further treatment. While the rhetoric appears overblown to some, I do believe there is a “Coming Depression Apocalypse” if ALKS 5461 is approved by the FDA.

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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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 second most abused drug of 2013.

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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“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.

06/17/15

The Coming Depression Apocalypse

© 3quarks | 123RF.com

© 3quarks | 123RF.com

According to the Motley Fool, the pharmaceutical company Alkermes has a potential blockbuster drug for treating major depression in its pipeline. Currently in Phase 3 clinical trials, ALKS-5461 is one step away from Alkermes filing for approval by the FDA. Mental Health Daily reported that ALKS-5461 was given fast track approval by the FDA and is expected to be available in 2016. Its projected use is as a supplementary treatment to current antidepressant drugs. But once approved, the “supplementary” element will likely stop because it’s new and fast acting. The problem is, the drug in ALKS-5461 that is supposed to treat depression is an opioid with addictive potential.

Before going further on this issue, we need to take a short trip into pharmacology and neurotransmitter function in order to understand what’s going on. There are proteins embedded within the membrane of a cell called receptors. These receptors receive chemical signals from outside the cell, and in turn produce a biochemical reaction inside the cell. The chemicals that bind and activate a specific receptor are called agonists. While an agonist causes a reaction, an antagonist blocks that reaction from occurring within the cell. It turns the cell off from the influence of the agonist.

Receptors are activated by either endogenous agonists (hormones or neurotransmitters), or exogenous agonists (drugs). Endogenous agonists are produced by the body. The endogenous opioid agonists include dynorphins, and the more widely known endorphins. If you want more information on biochemistry and neurotransmitter activity, try these Wikipedia pages for starters: opioid receptor, mu-opioid receptor, and agonist.

Opioids are known to have energizing and mood enhancing effects with some users. This effect seems to be associated with dynorphin, which is elevated in depression. Dynorphin is a full agonist for the kappa opioid receptor (KOR). Studies like that done by Knoll and Carlezon, “Dynorphin, Stress and Depression,” suggest that KOR antagonists may have a potential therapeutic potential in treating anxiety and depression. While this biochemical hypothesis makes sense to psychiatrist Daniel Carlat, in The Carlat Psychiatry Report, he was more reserved on the treatment potential of ALKS-5461 than Mental Health Daily and the Motley Fool.

The efficacy of ALKS-5461 for depression remains to be seen. Some trials of ALKS-33 alone have already been performed, particularly in the areas of alcohol dependence and binge-eating disorder. These have been negative.

Now let’s look at my concern with ALKS-5461. First, it is a combination of buprenorphine, and samidorphan, or ALKS-33. Buprenorphine is used in addiction treatment as a detoxification drug and in opioid maintenance therapy, where its brand names are Suboxone (buprenorphine with naloxone) and Subutex (buprenorphine without naloxone). Suboxone and Subutex are classified as Schedule III controlled substances, meaning they have a moderate to low potential for physical and psychological withdrawal. Other Schedule III drugs include ketamine and anabolic steroids.

Buprenorphine is a partial mu opioid agonist, meaning it displaces morphine, methadone, and other full opioid agonists from activating the mu opioid receptor (MOR). But it does not provide the same degree of receptor activation as the full agonists (It doesn’t get you as high), resulting in a net decrease of agonist effect and the onset of withdrawal if it used soon after a full agonist like heroin. Patients planning to begin Suboxone maintenance therapy are told to abstain from opioids for twenty-four hours before their first dose of Suboxone.

At lower doses and with individuals who are not dependent on opioids, both full agonists like heroin and partial agonists like buprenorphine will produce identical euphoric effects. Partial agonists like buprenorphine also have a ceiling effect, meaning that past a certain point, typically 12 to 16 mg, no difference in analgesia, euphoria and respiratory depression will be felt.

Buprenorphine does produce physical dependence. Reportedly, this is to a lesser degree than full opioid agonists; and it is supposed to be easier to discontinue at the end of medication treatment. While this is the received wisdom on websites like NAABT, The National Alliance of Advocates for Buprenorphine Treatment, that has not been the case for what I’ve observed clinically with individuals who have tried buprenorphine. Generally I’ve heard that buprenorphine is harder to kick than heroin. So ALKS-5461 will be treating depression with a drug that may be harder to kick than heroin.

Buprenorphine is also a full antagonist of the kappa opioid receptor (KOR), which underlies its use in ALKS-5461 as an antidepressant. If the production of dynorphine by KOR receptors increases with depression, theoretically then buprenorphine would block these receptors and limit the release of dynorphine—elevating the individual’s mood. Peter Tenore, in “Psychotherapeutic Benefits of Opioid Agonist Therapy,” said that opioids like buprenorphine could be “effective, durable and rapid therapeutic agents for anxiety and depression.”  The problem is with the partial agonist effect that buprenorphine has on mu opioid receptors (MOR) you can still use buprenorphine to get high.

That was the rationale for combining naloxone with buprenorphine in Suboxone. Naloxone is an opioid antagonist that counters the effects of opioids at the mu receptor, but doesn’t trigger a euphoric effect. Marketed under the brand name of Narcan, naloxone is used to counter the effects of opioids in overdose situations. The death of Phillip Seymour Hoffman led to calls for greater availability of naloxone (see “The Opioid-Heroin Cycle”) for individuals to use in overdose situations.

While naloxone is still the standard medication for emergency reversal of opioid overdose, its clinical use in long-term opioid addiction treatment is being superseded by naltrexone. Naltrexone (C20H23NO4) is structurally similar to naloxone (C19H21NO4), and samidorphan (C21H26N2O4). But it has a slightly increased affinity for κ-opioid receptors (KOR) and has a longer duration of action than naloxone. Naltrexone is used as a preventative medication for opioid use disorder in Vivitrol, whose marketing rights are owned by Askemet.

Samidorphan (ALKS-33) is also a full opioid antagonist, acting on the MOR receptor with mixed agonist-antagonist activity at the KOR receptor. Combining samidorphan with buprenorphine is supposed to block the agonist effect of buprenorphine on the MOR receptor, while not inhibiting the buprenorphine antagonist effect on the KOR receptor.  A study by Shram et al. comparing samidorphan to naltrexone was published online ahead of the June 2015 issue of the Journal of Clinical Psychopharmacology. Samidorphin was found to have greater binding affinity than naltrexone to mu receptors and a longer half-life. This was suggestive of prolonged opioid receptor antagonism at lower doses of samidorphin. The study, though, was funded by Askemet.

Suboxone (buprenorphine and naloxone) and ALKS-5461 (buprenorphine and samidorphin) appear to be biochemical twins. And it does not seem to me that the addictive potential of buprenorphine has been entirely neutralized by its combination with samidorphin as claimed. The history of abuse and diversion with Suboxone supports this concern. If my fear is true, then in the name of treating depression, ALKS-5461 will create a huge population of individuals who become dependent upon buprenorphine.

Coming off of buprenorphine is not fun. Here is a personal testimony of someone tapering off of buprenorphine. Oh, and mood swings with bouts of anxiety or depression are common side effects with buprenorphine withdrawal.

Buprenorphine withdrawal symptoms last longer for those who use buprenorphine for longer periods of time or at higher doses. Additionally, those who use buprenorphine other than prescribed (snort, inject, chew) may experience more severe symptoms than someone taking buprenorphine as prescribed. In these cases, physical buprenorphine withdrawal symptoms can last weeks after stopping.However, psychological withdrawal symptoms can last for many months after cessation. It is recommended that you join a support group or see a psychologist who can help see you through the protracted or post acute withdrawal symptoms (PAWS). Many heavy buprenorphine users experience PAWS. With continued use of buprenorphine, there comes a point where the brain produces in an inadequate amount of neurotransmitters in the body. People going through buprenorphine PAWS manifest long lasting changes in the brain as a result of long term use.

The Substance Abuse and Mental Health Services Administration (SAMHSA) estimated that in 2013, 1.8 million people had an opioid use disorder; 517,000 of which had one related to heroin use. SAMHSA also estimated that each year, 9.1% of the adult population experience symptoms consistent with major depression. One 2012 study suggested that 10% to 30% of individuals with major depression suffer from treatment resistant depression. Using a U.S. population estimate of 320.94 million, with a median 20% for individuals with treatment resistant depression, that leaves a target population of over 5.84 million Americans with treatment resistant depression. God help us.

I don’t think it is too strong rhetorically to speak of a pending depression apocalypse. I hope I’m wrong. But widespread use of ALKS-5461 could instigate a huge population of individuals dependent upon buprenorphine. And the problems coming off of ALKS-5461 would eclipse what we now know happens with SSRI withdrawal. Within the biochemical worldview, these symptoms will be reinterpreted as evidence of the underlying depression and proof the individual needs to remain on ALKS-5461. Sound familiar?