10/15/24

Is There a Better Way to Prevent Overdose Deaths?

The CDC released provisional data suggesting opioid overdose deaths dropped to the lowest level in three years. The newest CDC update indicated the provisional decline reflects data through April of 2024. An Associated Press report said experts reacted cautiously to the reported drop. It was only the second annual decline in more than 30 years, and it was also relatively small. One expert thought it should be understood more as a leveling off; another observed the previous decrease in 2018 was followed by an increase afterwards.

Nevertheless, the CDC Chief Medical Officer thought the dip was “heartening news,” but “there are still families and friends losing their loved ones to drug overdoses at staggering numbers.” A study reported in May of 2024 in JAMA Psychiatry found that an estimated 321,566 children lost a parent to drug overdose in the US from 2011 to 2021. The rate of children who lost a parent to drug overdose per 100,000 children increased from 27.0 per 100,000 to 63.1 per 100,000 in 2021. There were significant differences across racial and ethnic groups, with the highest rates among children of non-Hispanic American Indian or Alaska Native individuals, who had a rate of 187.1 per 100,000 in 2021. This was more than double the rate among children of non-Hispanic White individuals (76.5 per 100,000) and non-Hispanic Black individuals (73.2 per 100,000).

Given the potential short- and long-term negative impact of parental loss, program and policy planning should ensure that responses to the overdose crisis account for the full burden of drug overdose on families and children, including addressing the economic, social, educational, and health care needs of children who have lost parents to overdose.

According to the CDC, around 107,500 people died of overdoses in the U.S. in 2023, which was down 3% from 2022 when there were an estimated 111,000 such deaths. There have been more than 1 million drug overdose deaths since 1999. An August 14^th CDC update of that data had a graph that showed the 2018 leveling off was followed by a dramatic increase after the COVID-19 pandemic began in March 2020. See the following figure taken from the CDC update.

The update reported the overall decrease of overdose deaths in the U.S. was 12.2%. Yet the interactive maps indicated several Western states had overdose rates that were as high or higher than reported previously. Alaska (41.82%), Oregon (15.11%), Nevada (13.33%), and Washington (10.03%) all reported double digit increases. Utah, Wyoming, Colorado, Hawaii, and Iowa also reported increases. Nebraska (29.95%) and North Carolina (41.81%) had significant decreases. However, the “reported provisional counts may not include all deaths that occurred during a given time period.” These delays are because they require lengthy investigation, including toxicology testing.

Commenting on the same CDC update, CBS News reported at its peak last summer, the U.S. had more than 86,000 estimated deaths. This compared to the CDC estimate of 75,091 opioid overdose deaths for the year ending in April 2024. “The pace of opioid overdose deaths still remains far worse than before the pandemic, when there were fewer than 50,000 fatal overdoses a year.” Fatal overdoses from drugs other than opioids have been decreasing as well. But the individuals who overdosed aren’t the only victims.

Campaigning on Overdoses

Not surprisingly, CBS News noted how overdose deaths became part of the 2024 presidential campaign rhetoric. Former president Trump said overdoses were lower during his term. Technically, he was correct. The figures were lower during his tenure as the 45^th president of the United States from January 2017 to January 2021 than they are currently. But according to CDC data, the overdose increases began around March of 2019. During the Trump presidency, overdose deaths grew from 66,571 in the twelve months before January 2017 to 94,788 in the twelve months before January 2021, an increase of 29.8%.

The former president said he wanted to work with states to force homeless addicts into treatment and punish drug dealers with the death penalty. Both Trump and Harris have tied curbing drug overdoses to immigration and border issues. But Trump incorrectly claimed overdose deaths were up 18% “under Kamala.” Assuming he meant during the tenure for Joe Biden who became president in January of 2021, overdose deaths were reported to be 94,778 in January of 2021, and 97,309 in April of 2024, a 2.6% increase.

Notice that there was an effect of when the reported CDC data on overdose deaths was collected after the COVID-19 pandemic began. For example, at the time the WHO reported the beginning of the COVID-19 pandemic in March of 2020, there had been 74,679 overdose deaths in the previous 12 months. In March of 2021, there were 98,211 reported overdose deaths, an increase of 24% in the first year of the pandemic. This dramatic increase of overdose deaths in the first year of the pandemic occurred during the last year of Trump’s presidency.

The FDA first granted emergency use authorization to the Pfizer-BioNTech COVID vaccine on December 10, 2020, followed by the Moderna vaccine on December 17, 2020, and the Janssen vaccine on February 27, 2021. By April 19, 2021 all U.S. states had opened vaccine eligibility to residents 16 and over. By March of 2022, reported overdose deaths were 108,604 in the 12 previous months, an increase of 9.6%. By March of 2023, the previous 12 months of reported overdose deaths were 110,082, an increase of 1.4%. By March of 2024, reported overdose deaths were 100,518 for the previous 12 months, a decrease of 8.7%.

The variance of the increase in overdose deaths dropped from a high of 24% in the first year of the pandemic, to an increase of only 1.4% in 2023, and was followed by an 8.7% decrease in March of 2024, three years after the availability of the COVID vaccines in the U.S. This suggests it had nothing to do with who was president or vice president; or which political party was in power.

As noted above, there have been over a million overdose deaths since 1999. CDC data indicated there were 47,523 overdose deaths in the 12 months before January 2015, and 72,124 overdose deaths in the 12 months before January 2020, an increase of 34%. So, overdose deaths were a public health problem independent of the pandemic.

Preventing Overdose Deaths Through a Drug-Centered Model of MAT

In order to address this public health problem, the National Institutes of Health launched the HEALing Communities Study (HCS) in 2019. “It was the largest addiction prevention and treatment implementation study ever conducted.” It targeted 67 communities in four states (Kentucky, Massachusetts, New York and Ohio) that had been hit hard by the opioid crisis. The goal was to test the impact of an integrated set of evidence-based interventions for preventing overdose and treating opioid misuse in communities that were highly impacted by the opioid crisis.

The findings of the HCS study were published in the New England Journal of Medicine. The Communities That HEAL (CTH) intervention focused on a harm reduction approach, with education about overdose prevention and naloxone distribution, the use of methadone and buprenorphine to treat opioid use disorder, and safer opioid prescribing, dispensing and disposal practices. Yet, “despite the breadth and depth of the intervention, the risk of opioid-related overdose death was similar in the intervention group and the control group.” In other words, there were no statistically significant differences.

The researchers first said the time frame to implement the various strategies was insufficient. Secondly, they thought the COVID-19 pandemic reduced the capacity of communities to implement the Communities That HEAL (CTH) intervention. Thirdly, changes in the illicit drug market occurred with fentanyl becoming more prevalent, indications that it was used as an adulterant with stimulants and it also began appearing in counterfeit pills. Additionally, there were challenges from the growing use of xylazine in illicit opioids. For more information on xylazine, see “Tranq Dope and Its Consequences” and “Flesh Eating Tranq Dope.”

Attempting to put a positive spin on the disappointing results, a NIH news release from the National Institute on Drug Abuse (NIDA) in June of 2024 said that despite “unforeseen challenges,” the HCS successfully engaged communities to implement hundreds of evidence-based strategies, “demonstrating how leveraging community partnerships and using data to inform public health decisions can effectively support the uptake of evidence-based strategies at the local level.” The NIDA director, Nora Volkow said:

Yet, particularly in the era of fentanyl and its increased mixture with psychostimulant drugs, it’s clear we need to continue developing new tools and approaches for addressing the overdose crisis. Ongoing analyses of the rich data from this study will be critical to guiding our efforts in the future.

Then the leader of SAMHSA (Substance Abuse and Mental Health Services Administration) said:

This study recognizes there is no quick fix to reduce opioid overdose deaths. Saving lives requires ongoing commitment to evidence-based strategies. The HEALing Communities Study facilitated the implementation of 615 evidence-based practice strategies, with the potential to yield lifesaving results in coming years.

However, I believe an additional problem with the results of the HCS study was the various intervention strategies were based on a disease-centered model of drug action. NIDA and SAMHSA need to view MAT and opioid use disorder through the lens of a drug-centered model of medication action and adjust their intervention strategies accordingly.

Joanna Moncrieff describes two different types of drug action, the disease-centered model and the drug-centered model. The disease-centered model underlies the psychopharmacology presumed in current MAT. Its theoretical assumptions about how psychotropic drugs work are rarely discussed explicitly. This assumes psychotropic medications like buprenorphine help to correct a biochemical abnormality. For more on Moncreiff’s models of drug action, see “Rethinking Models of Psychotropic Drug Action.”

William White has tried for years to build bridges between the two philosophically-opposed positions on the use of MAT. In “From Bias to Balance,” he described them as “medication haters” and “medication advocates.” White said medications can play a valuable role in harm reduction, but we do addiction treatment a disservice if we portray medication alone as a panacea for the cure of opioid addiction, which seems to be what the HCS study did. He added:

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

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

There is no pharmacological difference between drugs used for psychiatric purposes and other recreational or psychoactive drugs. They all act on the nervous system to produce a state of altered consciousness, a state that is distinct from the normal undrugged state; a drug is a drug, is a drug. We need to develop a better way to prevent overdose deaths. The evidence-based interventions of HCS need to see their prevention attempts with MAT through the lens of a drug-centered model of drug action.

For more information on William White and the disease-centered versus the drug-centered models of drug action, see: “The Complexities and Limitations of Buprenorphine” Parts 1 and 2.

09/8/20

Growing Pains with Narcotics Anonymous

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

06/30/20

The Complexities and Limitations of Buprenorphine, Part 2

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

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

This notion, sometimes called the ‘chemical imbalance’ theory, is the implied view of SAMHSA, which says MAT medications (like buprenorphine) “operate to normalize brain chemistry.” But in a ‘drug-centered model’ the distinctive physiological, behavioral and subjective effects of drugs are used to define drug action. “The therapeutic value of a drug stems from the usefulness of these effects in clinical situations.”

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

06/23/20

The Complexities and Limitations of Buprenorphine, Part 1

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

02/26/19

More Harm Than Good with Baclofen

In October of 2018 French health authorities approved the use of a muscle relaxant known as baclofen as a medication-assisted treatment (MAT) for alcoholism. In the U.S., it is approved to treat muscle spasms caused by conditions such as multiple sclerosis or spinal cord injuries. But a French-American cardiologist names Olivier Ameisen self-treated his own compulsive drinking with high doses of baclofen and then wrote a book about his experiences: The End of My Addiction. His reasoning behind the book title was that since baclofen stopped his symptoms of craving and obsessing over alcohol, he was “cured” of alcoholism.

I wrote a three-part article, “The End of Alcoholism? “ (Part 1, Part 2, Part 3), about Ameisen and his use of baclofen as a MAT for alcoholism three years ago. Read that article for more information on Ameisen and his so-called “cure.” My primary concern discussed then was the known withdrawal syndrome related to baclofen use. Similar to medications used to “treat” opioid use disorders (buprenorphine and methadone) and anxiety or panic attacks (benzodiazepines like: Ativan, Klonopin, Xanax) the physical and psychological dependency that develops is a hidden adverse effect. The medications work so effectively that the growing dependency is either minimized or goes unnoticed. Only when and if the individual attempts to taper off of the drugs do people realize what has happened.

The Prescribers’ Digital Reference warns that confusion, hallucinations, seizures and other psychiatric disturbances have occurred with abrupt discontinuation (withdrawal) of baclofen. They recommended a gradual reduction over 2 weeks or more. Listed severe adverse reactions included: coma, stroke, seizures, suicidal ideation, and others. Milder and more frequent adverse reactions included: drowsiness, weakness, dizziness, headache, and others. There is a very long list of noted drug interactions, many of which are CNS (central nervous system) depressants like benzodiazepines and opioids.

The Medical Xpress press release announcement of France’s approval of baclofen did indicate officials warned the drug could have harmful side effects and limited its maximum recommended dosage to 80 milligrams. This was down from the 300-milligram dose that had been used previously by Ameisen and others. The French version of the U.S.’s FDA (ANSM) said that while there was not definitive proof baclofen was efficient in treating alcoholism, it has shown “clinical benefits in some patients.” The ANSM director said that refusing the drug “did not seem reasonable to us given the needs and the seriousness of alcoholism, and the fact that tens of thousands of people are taking the medicine for this treatment.”

In November of 2018 the British medical journal The Lancet published an editorial article by Agabio et al., “Baclofen for the treatment of alcohol use disorder: the Cagliari Statement.” The consensus statement was named after the town in Italy where the GABA_B Receptor Conference was held on May 25, 2018. Agabio et al. said they believed baclofen was a “promising pharmacotherapy for alcohol use disorder, but it’s superiority over placebo has not been established yet.” More research needed to be done.

Despite the absence of consistent evidence of efficacy, baclofen is frequently used off-label to treat alcohol use disorder, especially in Australia and some European countries. The use of baclofen for clinical research and in medical practice varies substantially, because of differences in treatment provision for alcohol use disorder, clinical experience, and country-specific regulations and culture.

Three recently published meta-analyses were cited and commented on in “Baclofen for the treatment of alcohol use disorder: the Cagliari Statement.” Agabio et al. said the studies did not draw definitive conclusions on the efficacy of baclofen to treat alcohol use disorder. One meta-analysis (Bschor et al.) did not find baclofen to be superior over placebo on the primary outcomes of each study. The other two meta-analyses (Rose and Jones; Pierce et al.) found baclofen increased the number of abstinent patients and time to first drink when compared to placebo. “Chiefly, all three meta-analyses found overall a small effect size and substantial heterogeneity among studies.”

Bschor et al. found a small, but not statistically significant superiority of baclofen over placebo. They questioned the utility of baclofen in the long-term treatment of alcohol use disorder at both normal and high doses. “While the confidence intervals indicate that marginally harmful or moderately beneficial effects of baclofen remain a possibility, the most likely effect size is slightly above placebo effects.”

Rose and Jones said baclofen was associated with higher rates of abstinence than placebo. But there was no superior effect of baclofen on increasing the number of abstinent days or decreasing heavy drinking, craving, anxiety or depression. “These results suggest that the current increasing use of baclofen as a treatment for alcohol use disorders is premature.”

Commenting on her study for Healio, Abigail Rose said many of the trials in her study were under-powered. There were also differences in how the trials reported data on adverse events. “Although the most recent trials were larger and still failed to find an effect of baclofen. Importantly, we don’t yet fully understand baclofen’s pharmacokinetics and how this may have an impact on therapeutic effect.”

Pierce et al. found that low dose baclofen (LDB 30-60 mg) showed better efficacy than high dose baclofen (HDB >60 mg daily). Tolerability of HDB was low, but serious adverse events were rare. The effects of baclofen were stronger when daily alcohol intake was higher. “Baclofen seems to be effective in the treatment of AD, especially among heavy drinkers. HDB is not necessarily more effective than LDB with low tolerability of HDB being an import limitation.”

Naudet and Braillon reflected on Agabio et al.’s article in the same issue of The Lancet, “Baclofen and alcohol in France.” They said the promotion of the off-label use of baclofen was not appropriate, “especially when evidence points to a negative benefit:harm ratio.” They noted where the ANSM published an evidence-based assessment “from a Temporary Special Scientific Committee of independent experts who concluded that the benefit:harm ratio of baclofen in alcohol use disorder was negative.” After two days of public hearings, the ANSM concluded that it supported the use of baclofen in alcohol-dependent patients, but limited the marketing authorization for baclofen proposed in the application of Ethypharm Pharmaceuticals to France. Then on October 23, 2018 the ANSM approved the use of baclofen for alcohol use disorder.

This decision seems to ignore the evidence summarised by the Temporary Special Scientific Committee. Evidence opposing the use of baclofen includes findings from a pharmacoepidemiological study on 277,790 patients who were treated with baclofen between 2009 and 2015. Compared with 117,720 people who used the approved treatments for alcohol disorders (acamprosate, naltrexone, or nalmefene), the group of 47,614 people who were prescribed baclofen for an off-label use had higher mortality at any dose of baclofen. . . . Importantly, this increased risk was dose related.

Referring to the Bschor et al. and Rose & Jones studies, Naudet and Braillon said the finding that baclofen may increase abstinence was largely driven by two small, short-term studies, while the two largest trials failed to show that baclofen was effective. “No other effects on treatment efficacy were observed.” Further, the Temporary Special Scientific Committee focused on two relatively large randomized controlled trials of baclofen versus placebo. In the analyses for one of the studies submitted for baclofen’s approval by ANSM, Ethpharm changed the primary outcome measure. The results of this study are still unpublished in the peer-reviewed literature even though it was completed in October of 2015.

Preliminary results presented at conferences showed a two times increase in mortality in the baclofen group and that 19 of 162 patients in the baclofen group and 60 of 158 in the placebo group received open-label baclofen before the end of the study. Although the study was funded by the French Department of Health, the sponsor (Paris Public Hospital Authority) contractually transmitted data to Ethypharm. The analyses that were done for the purpose of approval were performed by Ethypharm, and the primary outcome was changed.

Replying to Naudet and Braillon on behalf of the Cagliari group, Agabio, Sinclair and Leggio said the Cagliari Statement did not promote the off-label use of baclofen. Rather, since the off-label use of baclofen happens, they wanted to provide “objective statements on the available evidence and clinical use of baclofen in alcohol use disorder.” They thought their statements could be useful to clinicians using baclofen for patients with alcohol use disorder and by scientists planning baclofen-related research in alcohol use disorder. Protecting patients’ safety was paramount and the recent pharmacoepidemiological work mentioned by Naudet and Braillon was important. “The Cagliari Statement highlights the risks related to baclofen use, emphasises that side-effects and safety concerns might be dose dependent, and provides several safety-related statements and recommendations.”

So despite the French approval of baclofen as MAT, it does not seem the FDA should also approve it for use in the U.S. market. In fact, it appears the benefit:harm ratio suggests baclofen would do more harm than good if approved as a MAT in the U.S.

12/4/18

The Bondage of Buprenorphine

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

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

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

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

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

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

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

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

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

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

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

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

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

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

10/23/18

Feuding Ideologies, Part 3

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

10/16/18

Feuding Ideologies, Part 1

In August of 2017, the now former Health and Human Services Secretary, Tom Price, said he didn’t think it was necessary to declare the opioid epidemic to be a national emergency. This was despite the president’s own opioid commission recommending it as the “first and most urgent recommendation.” Two days later, the President reversed Price’s statement, saying: “The opioid crisis is an emergency, and I’m saying officially right now it is an emergency.” The response was mixed. While President Trump’s announcement could be used to help free up federal resources and help to prioritize responses to the disaster, it could also permit the administration to push for new sentencing legislation in order to get “tough on crime” related to drug use.

What isn’t disputed is that the U.S. does have a serious opioid problem and something needs to be done about it. Drug overdose is the leading cause of death in Americans under the age of fifty. Forecasts by STAT News are the annual death rate will increase by at least 35 percent by 2027. The CDC reported that from 2002 to 2015 there was a 5.9-fold increase in the overdose deaths from heroin and non-methadone synthetic opioids.

The latest statistics for the U.S. opioid epidemic is now available in the 2016 National Survey on Drug Use and Health (NSDUH). Among the myriad of statistics reported there was news that heroin users increased 230% from 2002 to 2016, while heroin deaths increased 630%. An estimated 948,000 people aged 12 or over reported they used heroin in the past year. That translates to .4% of the country’s population. There were also an estimated 11.5 million people who misused pain relievers in the past year, 4.3% of the population aged 12 or over. Combined, there are 11.8 million people who misused opioids, 4.4% of the population, in 2016.

The 2016 NSDUH Report can be accessed here. A shorter, graphic-based report of key findings, including those noted above, is here.

One of the treatment approaches often touted to address the opioid crisis is medication-assisted treatment (MAT) with Suboxone. In January of 2015, Jason Cherkis wrote “Dying To Be Free.” His subtitle asked why we weren’t using a treatment for heroin addiction—Suboxone—that actually worked. The opioid problem in Kentucky was the focus of his article, which I found to be rhetorically persuasive and well written. You are introduced to individual after individual who wouldn’t or couldn’t use Suboxone and ended up dead from an eventual overdose.

“Dying To Be Free” was a finalist for a Pulitzer in 2016 for its “deeply researched reporting on opioid addiction” that showed how many drug overdose deaths could have been prevented. The cover letter submitted for its entry for the Pulitzer by The Huffington Post said it triggered a series of state and federal policy changes that rejected abstinence for opioid misuse and embraced medication-assisted treatment. “‘Dying To Be Free’ offered readers an immersive experience that included audio and video documentaries and photo and data displays.”

This was not fake news. “Dying to Be Free” captured the agony of individuals and families who struggle with opioid misuse. But it also made abstinence-based approaches to treatment and recovery a bogeyman responsible for many of the unnecessary deaths from opioid overdoses. The rhetoric of the article was a straw man attack on abstinent-based treatment while it extolled MAT. Its biomedical treatment bias seemed to dismiss or ignore many of the problems with Suboxone as a MAT for opioid addiction. Nor did it tell the whole story behind Suboxone. It also misrepresented the recovery philosophy of self-help groups like Alcoholics Anonymous. Here’s what I mean.

In the last paragraph of his second chapter, Cherkis said: “There’s no single explanation for why addiction treatment is mired in a kind of scientific dark age, why addicts are denied the help that modern medicine can offer.” This succinctly captures the problem as he sees it with existing treatment approaches to the opioid crisis. Heroin addiction is a medical disease and should be treated as a medical disease. Modern medicine has a scientific treatment for heroin addiction that is resisted because of stigma, a deep-rooted adherence to self-help, and the criminalization of heroin addiction. If you question or oppose MAT, you are apparently mired in a kind of scientific dark age.

To enter the drug treatment system, such as it is, requires a leap of faith. The system operates largely unmoved by the findings of medical science. Peer-reviewed data and evidence-based practices do not govern how rehabilitation facilities work. There are very few reassuring medical degrees adorning their walls.

Dr. Mary Kreeft, one of the pioneers of methadone maintenance, was liberally quoted to support the medical model of addiction. She noted how opioid addiction alters multiple regions in the brain, including those that regulate reward, memory, learning, stress, hormonal response and stress sensitivity. According to Dr. Kreeft, after a long cycle of opiate addiction, a person needs specific medical treatment. Some people may be OK in time. But “the brain changes, and it doesn’t recover when you just stop the drug because the brain has been actually changed.”

An abstinence-only treatment that may have a higher success rate for alcoholics simply fails opiate addicts. “It’s time for everyone to wake up and accept that abstinence-based treatment only works in under 10 percent of opiate addicts,” Kreeft said. “All proper prospective studies have shown that more than 90 percent of opiate addicts in abstinence-based treatment return to opiate abuse within one year.” In her ideal world, doctors would consult with patients and monitor progress to determine whether Suboxone, methadone or some other medical approach stood the best chance of success.

This is a rigid, strict medical model of opioid addiction. And it gives a mixed message regarding whether or not the individual will ever be able to stop taking Suboxone or methadone. Neither drug, said Cherkis, is a miracle cure. But they buy addicts time to fix their lives, seek counseling and allow their brains to heal. So far, so good. But here comes the caution: Doctors recommend tapering off the medication cautiously. The process could take years, as addiction is a chronic disease and effective therapy takes time. Then comes the typical analogy of the pure medical model of addiction:

Doctors and researchers often compare addiction from a medical perspective to diabetes. The medication that addicts are prescribed is comparable to the insulin a diabetic needs to live.

There is no mention of neuroplasticity—the brain’s ability to reorganize itself by forming new neural connections. “Neuroplasticity allows the neurons (nerve cells) in the brain to compensate for injury and disease and to adjust their activities in response to new situations or to changes in their environment.”

Jeffrey Schwartz and Rebecca Gladding use an almost identical description of neurological action to that given above by Dr. Kreeft to describe how to change the brain; to modify bad habits (including addiction) and unhealthy thinking. In You Are Not Your Brain, they describe how we teach our brains to act in unhealthy ways. The brain does not distinguish between beneficial and destructive habits, “it just responds to how you behave and then generates strong impulses, thoughts, desires, cravings, and urges that compel you to perpetuate your habit, whatever it may be.”

Clearly, the brain can exert a powerful grip on one’s life—but only if you let it. The good news is that you can overcome the brain’s control and rewire your brain to work for you by learning to debunk the myths it has been so successfully selling you and by choosing to act in healthy, adaptive ways.

Neuroplasticity, as described by Schwartz and Gladding, does not reject Kreeft’s neurological description of addiction. But it does say it isn’t the whole story. An ideology of addiction as a purely biomedical condition seems to permeate “Dying To Be Free.” Addiction, when conceived strictly as a brain disease, rejects or ignores the non-scientific construct of mind. If we are conceived as only biological beings, then addiction is explained and treated within a biomedical worldview. Any treatment approach to addiction not based on this premise is therefore faulty.

Drug treatment facilities were said in “Dying To Be Free” to “generally” fail to distinguish between addictions. They have a one-size-fits-all approach. Addicts in residential treatment experience a “hodgepodge” of drill-instructor tough love and self-help lectures. Programs appear simultaneously excessively rigid and wildly disorganized. “And with roughly 90 percent of facilities grounded in the principle of abstinence, that means heroin addicts are systematically denied access to Suboxone and other synthetic opioids.”

After describing two older, drug treatment programs with a therapeutic community model of care that used coercive techniques—Synanon and Daytop (Drug Addicts Yield TO Persuasion)— he said:

The number of drug treatment facilities boomed with federal funding and the steady expansion of private insurance coverage for addiction, going from a mere handful in the 1950s to thousands a few decades later. The new facilities modeled themselves after the ones that had long been treating alcoholics, which were generally based on the 12-step methodology. Recovering addicts provided the cheap labor to staff them and the evangelism to shape curricula. Residential drug treatment co-opted the language of Alcoholics Anonymous, using the Big Book not as a spiritual guide but as a mandatory text — contradicting AA’s voluntary essence. AA’s meetings, with their folding chairs and donated coffee, were intended as a judgment-free space for addicts to talk about their problems. Treatment facilities were designed for discipline.

In support of this claim, Cherkis referred to a 2012 study conducted by the National Center on Addiction and Substance Abuse at Columbia University. It apparently was a reference to “Addiction Medicine: Closing the Gap between Science and Practice.” He said the study concluded the U.S. treatment system was in need of a “significant overhaul” and questioned whether the low levels of care received by addiction patients constituted a from of medical malpractice.

While medical schools in the U.S. mostly ignore addictive diseases, the majority of front-line treatment workers, the study found, are low-skilled and poorly trained, incapable of providing the bare minimum of medical care. These same workers also tend to be opposed to overhauling the system. As the study pointed out, they remain loyal to “intervention techniques that employ confrontation and coercion — techniques that contradict evidence-based practice.” Those with “a strong 12-step orientation” tended to hold research-supported approaches in low regard.

The Columbia University study did state a significant overhaul was needed in current treatment approaches; and it raised the question if the insufficient care received by addiction patients constituted “a form of medical malpractice.” It also pointed to the need for medical schools to “educate and train physicians to address risky substance use and addiction.” Unsurprisingly, it went on to say that all aspects of stabilization and treatment with addictions should be managed by a physician “as is the case with other medical diseases.” Remember that the Columbia study and Cherkis were both advocating for a physician-centered, medical model approach to addiction treatment.

However, I couldn’t find where it was supposed to have said the majority of front-line treatment workers were low-skilled and poorly trained. There was a section stating that physicians and other health professionals should be on the front line addressing addiction. Then it said: “Paraprofessionals and non-clinically trained and credentialed counselors can provide auxiliary services as part of a comprehensive treatment and disease management plan.”

It did not say the majority of front-line treatment workers were low-skilled and poorly trained “incapable of providing the bare minimum of medical care.” Yet in the case study examples found in “Dying To Be Free,” that is what Cherkis presented. The Columbia study did cite another study, which found that recovering support staff had little enthusiasm for evidence-based practices. “They also were more likely to support intervention techniques that employ confrontation and coercion–techniques that contradict evidence-based practices.” But these paraprofessionals only made up “24 percent of the treatment provider workforce.”

Cherkis seems to have mis-remembered what the Columbia study actually claimed in this matter. I wonder if, because of his commitment to a strictly medical model ideology for opiate treatment, he was reading into the study. His quote above supported the description of the treatment facilities he highlighted in his article, but wasn’t found by me in the article he cited on the Columbia study.

Another example of how his treatment ideology distorted his portrayal of Suboxone treatment was with how he described Hazelden’s Suboxone treatment program. “Dying To Be Free” mentioned that Hazelden, now the Hazelden Betty Ford Foundation, developed its own Suboxone treatment program for opioid addicts. But it failed to note this wasn’t accompanied by a rejection of “Twelve Step practices.” Within “The History of Hazelden,” on the Hazelden Betty Ford Foundation website, was the statement of how it “integrates the cornerstone Twelve Step practices of mutual support along with multidisciplinary clinical care, evidence-based therapies and the latest research in brain science.” Why weren’t there some case study examples from Hazelden in “Dying To Be Free”?

The facilities Cherkis highlighted in Kentucky were not representative of abstinent-based addiction treatment centers in the U.S.; ones that use the 12 Steps to structure their treatment program. In reading “Dying To Be Free” I see an underlying ideology of conceiving and treating addiction, specifically opiate addiction, through a strict biomedical lens. That is not the whole story of addiction. As a result, the rhetoric of the article constituted a straw man attack on abstinent-based treatment while it extolled MAT. This bias presents readers with an implied choice, a dichotomy, between Suboxone as an MAT for addiction and 12 Step, abstinent-based treatment. Ironically, Hazelden, an historically important treatment center that pioneered 12 Step, abstinence-based treatment, did not choose MAT over the 12 Step-based treatment, but combined the two. But you don’t get that information in “Dying To Be Free.”

Part 2 and Part 3 of this article will look at how “Dying To Be Free” misrepresented the recovery philosophy of self-help groups like Alcoholics Anonymous; and skimmed over the problems with MAT, specifically Suboxone.

07/24/18

Doubling Up On Depression

Alkermes seems to be presenting contradictory opinions when it comes to promoting two of its drugs. When discussing Vivitrol, its extended release injectable version of naltrexone, Alkermes refers to it as “nonaddictive.” This is in contrast to other FDA-approved addiction medications such as methadone or buprenorphine, which are opioids. Alkermes has also persisted in its attempts to get ALKS 5461 approved by the FDA as an adjunctive medication to treat major depression. The active ingredient in ALKS 5461 is buprenorphine and Alkermes has emphasized that upon discontinuation of ALKS 5461 there was no evidence of withdrawal.

The conundrum is rhetorically-based and not scientific. Buprenorphine is classified as a Schedule III controlled substance, meaning it has “a moderate to low potential for physical and psychological dependence.” Yet when ALKS 5461 is being promoted, research findings conclude “There was no evidence of withdrawal upon discontinuation of treatment with ALKS 5461.” Michael Thase, the Alkermes poster presenter for ALKS 5461 at the 2018 American Psychiatric Association annual conference was quoted by Healio as saying, “there was essentially no hint whatsoever of opiate-like withdrawal or discontinuation symptoms.”

But when buprenorphine is a medication-assisted treatment (MAT) in competition with Vivitrol, it is described by Alkermes and its lobbyists as being addictive in contrast to naltrexone, the ingredient in Vivitrol, which is not addictive. STAT News published an article written by Daniel Wolf, the director of international harm reduction development at the Open Society Foundation. Wolf cited and linked investigations by the New York Times, National Public Radio and ProPublica noting how Alkermes promoted Vivitrol at the expense of other MAT drugs like buprenorphine. One example, found in the NPR article, was where the Indiana Senate passed a bill approving the use of “a federal Food and Drug Administration-approved long acting, nonaddictive medication for the treatment of opioid or alcohol dependence.” The only drug approved by the FDA that meets that description is Vivitrol.

An investigation by NPR and Side Effects Public Media has found that in statehouses across the country, and in Congress, Alkermes is pushing Vivitrol while contributing to misconceptions and stigma about other medications used to treat opioid addiction.

Wolfe noted for STAT News that the investigations he cited showed how Alkermes marketers and lobbyists derided the daily administration of methadone and buprenorphine. The pitch is apparently working, as the sales of Vivitrol rose 600% between 2011 and 2017. Legislators in 15 states have written Vivitrol (by brand name) into their laws. And multiple jurisdictions now require drug offenders to agree to use the medication if they want to avoid imprisonment. In effect, state established Drug Courts have become “Vivitrol courts.”

Alkermes highlighted Vivitrol’s properties as an opioid antagonist. This means it blocks (instead of activating) the effects of opioids like methadone, burpernorphine and heroin on opioid receptors in the brain. Naltrexone, the active ingredient in Vivitrol, will not get you high. Methadone and buprenorphine can be used alone or in conjunction with other drugs to produce a high. Their differences as MAT treatment are illustrated in the following graphic, which was found in the NPR article.

Turning to ALKS 5461, we see that Alkermes had a series of setbacks as it attempts to have the FDA approve ALKS 5461 as an adjunct treatment for major depression. As FierceBiotech noted, Alkermes failed to meet their primary endpoints in two of three phase 3 clinical trials for ALKS 5461. “But Alkermes used the success of the third trial to paint the overall dataset as supportive of the efficacy of ALKS 5461.” What Alkermes did is use its statistical analysis of the second failed clinical trial (FORWARD-4) to discover a significant result within a subpopulation of the study that wasn’t targeted by its primary endpoint. They then modified their methodology and analysis of the third clinical trial (FORWARD-5) to match the post-hoc analysis and it successfully showed a statistical significance.

In previous articles, “Nearsighted Drug Development” and “The ‘Hotel California’ Effect,” I said this seemed like cheating, even though it was allowed. Alkermes then wanted the FDA to count its failed FORWARD-4 trial as a successful one, based on its post hoc statistical analysis. So far the FDA hasn’t bought the Alkermes attempts to justify its claims. In late January of 2018 Alkermes submitted a New Drug Application to the FDA for ALKS 5461. The company claimed ALKS 5461 “demonstrated a consistent profile of antidepressant activity, safety and tolerability in the adjunctive treatment of MDD.”

Then on April 2, 2018, the FDA informed Alkermes it was refusing to review the NDA application for ALKS 5461, saying there was “insufficient evidence of overall effectiveness for the proposed indication.” They wanted to see “additional well-controlled clinical trials” prior to the resubmission of ALKS 5461, disagreeing with the Alkermes attempt touse the success of the third trial to the overall dataset as supportive of ALKS 5461 efficacy. The FDA also wanted a bioavailability study to generate more bridging data between ALKS 5461 and buprenorphine. Alkermes disagreed with the FDA’s conclusions and planned to request a Type A meeting where they could clarify what additional information the FDA needs. FierceBiotech said:

The FDA’s refusal to buy into that line of thinking is a blow to people in Alkermes and beyond. Having talked up the strength of the dataset, Alkermes CEO Richard Pops and his colleagues emerge from the setback with dented reputations. More broadly, the FDA’s refusal to even review the data is a blow for any biotech hoping the arrival of Scott Gottlieb, M.D., as commissioner would usher in an era in which the FDA waves through drugs with patchy data packages.

Two weeks later, the FDA rescinded its refuse-to-file letter. FierceBiotech said: “The company did not provide the FDA with additional data or analyses and the agency expects to return a decision by Jan. 31, 2019.” Alkermes CEO Richard Pops said the FDA’s initial refusal was based on a “misunderstanding” of the NDA submission. He declined to say what the FDA initially thought was missing from the NDA. “I think it just took a while to get that lens focused the right way for FDA to accept the file.”

While ALKS 5461 is back on schedule, the FDA’s about-face is by no means a guarantee of success—the agency has deemed the data complete enough for review, but could still reject it.

At the May 2018 American Psychiatric Association Annual Meeting, Alkermes presented a poster on its research into the “Long-Term Efficacy, Safety and Tolerability of Adjunctive ALKS 5461 in Patients With Major Depressive Disorder.” The reported results of a completed long term study (NCT02141399) were that 49% of the 1454 enrolled patients completed the 1-year study, 11% discontinued due to an adverse event. The remission rate, defined as a score of 10 or less on the MADRS-10, was 52.5%. Time to remission was 59.0 days. Adverse events occurring with a frequency of less than 10% were nausea, headache, constipation, dizziness and somnolence (drowsiness). “There was no evidence of withdrawal upon discontinuation of treatment with ALKS 5461.”

Overall, ALKS 5461 showed durability of antidepressant effect up to 52 weeks of treatment in patients with MDD. ALKS 5461 was well tolerated with an AE profile consistent with that reported in the short-term trials.

These results were repeated in Healio: “ALKS 5461 well-tolerated in major depression” and in Psychiatry Advisor: “Novel Buprenorphine Combinayion Therapy Shows Efficacy for MDD in Long-Term Trial.” Psychiatry Advisor has links to the Alkermes clinical trials referenced, which are all completed, but none had reported their results by June 1, 2018. Michael Thase’s report in Healio seemed to be in conflict with the research program noted above by FierceBiotech, unless he was counting the recently completed long term study. He said: “The research program for this compound has included a number of double blind studies, of which two are unequivocally positive; these data are being reviewed by the FDA for a possible indication as an adjunct to antidepressants.”

FierceBiotech pointed out where two of three clinical trials phase 3 clinical trails failed to meet their primary endpoints. And the third had its methodology and analysis modified after post-hoc analysis of the second clinical trial showed statistical significance in a subpopulation. Can the results be “unequivocally positive” when the primary endpoint for one of the positive studies was changed after it had begun?

There are some questions I have with regard to the assertion there was “no evidence of withdrawal upon discontinuation” for the long term study. What specifically were the researchers looking for as “evidence of withdrawal”? And when was the assessment done—immediately upon conclusion of the 52-week study?

Mood swings with bouts of anxiety or depression are common side effects with buprenorphine withdrawal. Granted, the buprenorphine dose is relatively small at 2 mg, but the time period of use at 52 weeks was long. “Buprenorphine withdrawal symptoms last longer for those who use buprenorphine for longer periods of time or at higher doses.” See “A Double-Edged Drug” for more on buprenorphine withdrawal.

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. These changes are slower to reverse and can persist for many months, depending on the frequency and amount of past dosing.

Another thing to remember is that Suboxone (buprenorphine and naloxone) and ALKS 5461 (buprenorphine and samidorphin) appear to be biochemical twins. Also remember where employees of Alkermes have characterized buprenorphine as “addictive.” And the addictive potential of buprenorphine has not been entirely neutralized by its combination with Alkermes’ patented opioid antagonist, samidorphin (ALKS 33).

In “The Coming Depression Apocalypse,” I said I’m concerned the use of ALKS 5461 for treatment resistant depression would generate a population of individuals dependent upon buprenorphine. The problems coming off of ALKS 5461 would eclipse what we now know happens with SSRI withdrawal. A New York Times article said originally, antidepressants were supposed to be used short term for episodic mood problems—six to nine months. Now, almost 7% of Americans have been using antidepressants for at least five years. Patients who try to taper off antidepressants often find withdrawal symptoms are so severe they cannot stop. “Nearly half who tried to quit could not do so because of these symptoms.”

Coupling buprenorphine withdrawal in ALKS 5461 to the known issues with antidepressant withdrawal compounds the problems these medications were supposed to treat. And 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 and/or antidepressants.

04/5/16

I Smell a RAT

Medication Assisted Treatment (MAT) for addiction comes in various forms that are often (unhelpfully) lumped together into one category. Replacement or substitution methods, like methadone or Suboxone maintenance are radically different from using naltrexone to treat alcohol or opioid use disorders. Yet they are combined into the single category of MAT. While naltrexone is not a cure for addiction, it has been shown to help minimize cravings for urges for both alcohol and opioids. And there is some evidence emerging that it could be useful to blunt cravings for methamphetamine.

In 2010 Karlia et al. did a literature review on pharmacological approaches to treat methamphetamine use disorders. They concluded there was no substantial evidence for effective treatment at the time. “Clinical trials using aripiprazole [Abilify], GABA agents (gabapentin [Neurontin], baclofen, vigabatrin), SSRIs, ondansetron and mirtazapine [Remeron] have failed to show efficacy.” They noted where there was some indication where “agonist replacement medications” like d-amphetamine and modafinil may hold some promise.

The unavoidable problem with “treating” methamphetamine addiction with d-amphetamine is you are using a similarly addictive substance to “treat” methamphetamine addiction. Again, it repeats the error of opioid substitution/replacement therapy. While methamphetamine and amphetamine are Schedule II controlled substances, Modafinil still has an addictive potential as a Schedule IV. It is used to treat narcolepsy and shift work disorder, and it is touted as a “life hack” on Wall Street or “smart pill”—until you decide to stop taking it.

They also pointed to the work of Swedish researcher, Nitya Jayaram-Lindström, who showed in a 2005 study where naltrexone significantly reduced the subjective effects of dexamphetamine and blocked cravings in dependent patients. Additionally, the frequency and amount of amphetamine use was significantly reduced. A double blind study by Jayaram-Lindström in 2008 again showed the efficacy of naltrexone in reducing cravings and self-reported use of amphetamine. A further double-blind, placebo-controlled study by Jayaram-Lindström again demonstrated a significant reduction in cravings and self-reported use of amphetamine. “Naltrexone therefore appears to be a highly promising medication for amphetamine dependence.”

Now there is a study by UCLA researchers on naltrexone as a treatment for methamphetamine addiction. Here is a link to a pre-publication manuscript of the study by Ray et al. Again it was found that naltrexone blunted cravings for methamphetamine and lowered self-reports of subjective effects. Lara Ray, a UCLA psychology professor said: “The results were about as good as you could hope for.” The UCLA press release on the study and an article on The Fix by Zachary Siegel noted where clinical trials into the efficacy of naltrexone to treat methamphetamine addiction have already begun.

One clinical trial with naltrexone was completed and last updated in May of 2013 but no results are posted yet; and another study is ongoing. Although results for the complete trail by California Pacific Medical Center Research Institute were not posted on Clinicaltrails.gov, it does seem to be reported in a 2015 study by Pal et al. reported in the Journal of Addictive Medicine. There was not an improved treatment response found in this study. The Pal et al. study was quite small and does not really argue against further clinical trials into the potential use of naltrexone to treat methamphetamine addiction. The replication of Jayaram-Lindström’s results by Ray et al. are sufficient to see further research into this potential treatment.

The side effects from naltrexone are minimal, making it a viable medication to assist addicts trying to establish and maintain abstinence from dependence upon alcohol, opioids, and now—apparently—methamphetamine. Substitution or replacement medications for addiction need to be distinguished from other medications such as naltrexone within the catchall category of MAT. Perhaps they would be better labeled as SAT—Substitute Addiction Treatment—or RAT—Replacement Addiction Treatment—instead of MAT, Medication Assisted Treatment. Personally, I’m partial to RAT.

Faith Seeking Understanding

Charles Sigler, D.Phil.

Tag: MAT