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.”

06/23/20

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.

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.

11/30/15

The Seduction of Opioid Substitution

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Heroin and prescription opioid abuse is a widely recognized public health crisis in the United States. In 2014, Attorney General Eric Holder referred to overdose deaths from heroin and other prescription pain-killers as an “urgent public health crisis.” The CDC reported that heroin use more than doubled among young adults between 18 and 25 over the past ten years. Forty-five percent of the people who use heroin are also addicted to prescription opioids.

A July 2015 “Morbidity and Mortality Weekly Report” report by the CDC recommended a comprehensive response to this public health crisis. The recommendations included: reducing inappropriate prescribing and use of opioids, stronger prescription drug monitoring programs, improved access to evidence-based substance abuse treatment—including medication-assisted treatment for opioid use disorders and greater access and training in the use of naloxone to treat overdoses. There have been several steps taken towards making these recommendations a reality. For example, on November 18, 2015, the FDA approved the first nasal spray version of naloxone hydrocloride: Narcan nasal spray. But not all of the proposals have the same potential to free the individuals caught up in the opioid health crisis.

And legislation has been introduced in the Senate to “combat the opioid crisis.” “The Opioid and Heroin Epidemic Emergency Supplemental Appropriations Act” would dedicate $600 million to this crisis. About $250 million would support programs related to prevention, treatment and recovery. Another $200 million would fund local and state law enforcement programs. Fifty million would go toward the CDC; and $35 million would go to NIDA to monitor prescription drug programs and do targeted research on drug addiction. “We are losing lives daily and our first responders, healthcare providers and criminal justice system are overwhelmed.”

I’m not a fan of increasing the use of opioid maintenance medications such as methadone and buprenorphine because they’re “treating” an opioid addiction with addictive opioids. And I’m concerned that in the midst of the existing health crisis, increased access to such treatment seems to be indiscriminately promoted as the most effective “treatment” approach. Sometimes the studies of medication-assisted treatment fail to consider the negative consequences to individuals when promoting opioid substitution treatment. And sometimes studies that suggest the “effectiveness” of opioid maintenance have a biased interpretation of their results. Often what emerges is a program for the social control of addicts rather than one that helps them establish and maintain a recovery-oriented lifestyle. Here is an example of one such study.

The National Institute on Drug Abuse (NIDA) turned a “Science Spotlight” on a new study that looked at intervention approaches for opioid dependent patients in emergency departments (ED). The idea is a good one—developing an intervention for ED medical personnel to help opioid-dependent patients get into treatment. But what it doesn’t make clear is that the “treatment” is primarily ongoing participation in opioid substitution treatment.

This study showed that patients who received buprenorphine, along with a brief intervention to discuss opioid use, and up to 12 weeks of buprenorphine maintenance, were more likely to get follow-up addiction treatment and had reduced self-reported illicit opioid use. In addition, they were also less likely to need inpatient addiction treatment services, saving treatment costs. This adds to the growing body of literature suggesting that opioid-dependent patients may benefit from immediate initiation of medication while awaiting more comprehensive substance use disorder treatment.

Let’s take a closer look at the study by D’Onofrio et al. to see if it truly lives up to the endorsement it received from NIDA.

The primary outcome was what the researchers called “engagement in treatment.” This was defined as being enrolled in and receiving formal addiction treatment on the 30th day following randomization. “Formal addiction treatment” could include a range of clinical settings such as an opioid treatment program, such as a methadone clinic, inpatient or residential treatment and outpatient services. The outpatient services could be intensive outpatient programs and “office-based physicians who prescribe buprenorphine or other forms of medication-assisted treatment.”

The patients in the buprenorphine group of the study received buprenorphine in the hospital and take-home doses of buprenorphine to last until a scheduled appointment in the hospital’s primary care center, which was within 72 hours of their placement in the group. The buprenorphine patients continued to receive office-based burprenorphine treatment for 10 weeks. At that time they were transferred to a maintenance treatment program or a clinician for ongoing treatment. If they preferred, they were offered a 2-week detoxification.

In the buprenorphine group, 78% of the patients were still engaged in treatment at the thirty-day follow-up. Only 37% of the referral only group and 45% of the brief intervention and referral group were engaged in treatment. But remember what the study considered as “treatment.” Any patient in the buprenorphine group who was still active in the free, office-based treatment after 30 days would have been counted as “still engaged in treatment.” And they would have had another 40 days of free buprenorphine coming.

There was no information or data available on any of the groups beyond the thirty-day follow-up. So there was no clear indication if the patients in the buprenorphine group remained in treatment beyond the 10 weeks of the study’s subsidy of their substitution treatment. If the goal was to eventually engage individuals in more comprehensive treatment services, this “interim opioid agonist treatment,” should not have been lumped in with others as the outcome measure of “formal addiction treatment.” The failure of the researchers to distinguish this level of care from the others confounds the findings within the study’s primary outcome measure.

These patients had buprenorphine treatment initiated before they left the hospital. They also had an appointment scheduled within 3 days of their initial dose, with sufficient take-home medication to prevent any withdrawal until that appointment time. The other two groups did not receive any medication and so were on their own medically until they made an appointment and became engaged in treatment. They were sitting ducks for resuming the illicit opioid use that initially brought them to the ED. So the deck was staked in favor of the primary outcome measure.

Additionally, the buprenorphine care in the study was provided at no cost to the patients. The researchers dismissed this as a potential bias in their study, saying that 80% of the study’s patients had health insurance. However there are potential cost issues in health insurance despite the authors’ dismissal. Buprenorphine maintenance treatment is not always covered by insurance, as it is considered a “niche” medicine by insurance plans, as it is approved solely for the treatment of opioid dependence. Insurance companies predict that a limited number of their covered clients will need or use it. When there is coverage, there can be high co-pays. Insurance may pay for the prescription but not the office visits. Some Suboxone doctors don’t take insurance.

A secondary outcome measure for the study was self-reported use of illicit opioids. The buprenorphine group reported greater reductions in the mean number of days of illicit opioid use, from 5.4 days per week to .9 days per week. Patients in the referral group decreased from 5.4 days per week to 2.3 days; and the brief intervention group went from 5.6 days to 2.4 days. Remember that the buprenorphine group was treated with medication (buprenorphine) that forestalled withdrawal symptoms from the time they were placed in that treatment group while still in the hospital ED. Also, all three groups reduced their illicit opioid use over time. Comparing the buprenorphine treatment group to the others indicated that even with the medication, there were only 1.4 or 1.5 days less per week of illicit opioid use in the buprenorphine group.

Finally, the decreased use of inpatient treatment by the buprenorphine group was to be expected. The withdrawal symptoms that often precipitate detoxification or residential treatment were being addressed by the buprenorphine.

It has long seemed to me that the so-called harm reduction approach of opioid substitution treatment is more social control than actual treatment aimed at helping the individual addict to establish and then maintain sobriety. The positive outcomes and effects that are highlighted are typically things like lowered costs for residential treatment; lowered ED visits and costs; decreased drug-related crime.

There is proposed legislation, the Recovery Enhancement for Addiction Treatment Act, which would broaden the definition of a qualifying practitioner to include certain nurse practitioners or physician assistants and doctors with a board certification from the American Board of Addiction Medicine. The number of patients that a qualifying practitioner could dispense buprenorphine to within their first year would increase from 30 to 100. After one year, qualifying physicians could request approval to treat an unlimited number of patients under specified conditions. Writing about this proposed bill for the Huffington Post, James Charkis said:

The consensus among the medical establishment is that medically assisted treatments such as buprenorphine (and methadone), along with counseling, represent the best chance for addicts to gain a foothold on sobriety. Both medications can make withdrawal less painful and can significantly diminish further cravings for opioids — greatly reducing the chance of relapse.

One of the problems as I see it is that this “best chance” description is often mostly rhetoric. The “along with counseling” add-on becomes more window dressing than reality. Even where there is a tighter requirement for Suboxone patients to be active in some kind of counseling, individuals either fall through the cracks with counseling or just take up space because their presence in counseling is required for them to get what they really think will “treat” them—their Suboxone. Some individuals merely want Suboxone handy in case they can’t get any heroin or their opioid of choice to get high. Others want it to sell on the street to make some cash.

There is a place for opioid substitution treatment as we attempt to address the opioid health crisis. But the potential adverse consequences to the individual receiving the treatment need to be more clearly communicated. And studies of its “effectiveness” need to look beyond just the social benefits and the ability of opioid substitution treatment to seduce addicts into a more socially controlled form of opioid use.

Faith Seeking Understanding

Charles Sigler, D.Phil.

Tag: medication-assisted treatment