Medication Assisted Treatment: Buprenorphine — history, overview, pros and cons

buprenorphine

What Is Buprenorphine?

According to the pharmaceutical encyclopedia Drugs.com [1], buprenorphine is “an opioid medication” that is “used to treat opioid addiction (either prescription or illegal drugs), as part of a complete treatment program that also includes counseling and behavioral therapy.” It is also “used to treat moderate to severe pain.”

Brand names: Buprenorphine — Belbuca, Subutex, Sublocade, Butrans, Probuphine. Buprenorphine combined with naloxone — Suboxone, Zubsolv, Cassipa, Bunavail

Forms: According to the official publication of the American College of Emergency Physicians [2], buprenorphine sublingual tablets and film strips are “the primary formulation used in the emergency department and hospital as well as the most common form for those prescribed (it) for the treatment of opioid use disorder.” Injectable buprenorphine — Buprenex — is used as both an analgesic and in the treatment of opioid use disorder. Butrans, in the form of transdermal buprenorphine patches, is “used to treat chronic pain.” Probuphine “is a long-term implantable form of buprenorphine that delivers a continuous, stable blood level of (buprenorphine) for the treatment of OUD.” Sublocade is a subcutaneous monthly injection that “is the newest long-acting form of (buprenorphine) on the market, FDA-approved in late 2017 for treating OUD.”

Buprenorphine: History

buprenorphineAccording to the paper “The History of the Development of Buprenorphine as an Addiction Therapeutic,” published in 2012 in the Annals of the New York Academy of Sciences [3], buprenorphine was first synthesized in 1966 in the research laboratories of the British-based company Reckitt and Colman, where chemist John Lewis spearheaded the project. Lewis’ mentors included Robert Robinson, who “elucidated the active structure of morphine in 1925,” and Kenneth Bentley, whose work with the company McFarlan Smith (“the main U.K. producers of opium alkaloids”) laid the foundation for the Reckitt project.

According to a 2019 peer-reviewed article by Jai Ahluwalia [4], Lewis and his team “believed that ‘opioids with structures substantially more complex than morphine could selectively retain the desirable actions whilst shedding the undesirable side effects,’ and their main goal was to find such an opioid. They had two failed attempts before finally putting buprenorphine into clinical studies.” Reckitts shared buprenorphine with the Lexington, Kentucky-based Addiction Research Center (ARC) throughout the 1970s, where researchers “went on to study buprenorphine as a potential addiction treatment drug because of its combination of analgesic (agonist) and antagonist properties.” [3]

In 1978, Dr. Donald Jasinski of the ARC published a paper [5] that was ahead of its time, given that it would be several more decades before buprenorphine became widely used in the addiction treatment field: “Little if any physical dependence of clinical significance was produced by buprenorphine,” Jasinski wrote. “In man, buprenorphine has less intrinsic activity than morphine, and as such, has a low abuse potential. Moreover, the drug has potential for treating narcotic addiction since it is acceptable to addicts, is long-acting, produces a low level of physical dependence such that patients may be easily detoxified, is less toxic than drugs used for maintenance therapy, and blocks the effects of narcotics.”

So why did it take so long for buprenorphine to come to market? “Buprenorphine faced many hurdles, including scheduling issues; reluctance of pharmaceutical companies to take on addiction medicaments; fall-out from experiment, diversion, and abuse of its analgesic form; and still restrictive addiction treatment systems. As with methadone maintenance, many within the addiction research enterprise had become convinced of buprenorphine’s uniqueness as an opioid addiction treatment. However, the social and political context was quite different, given the maturity of the drug regulatory apparatus, the changing knowledge base in the field, and what had been learned from the experience of methadone maintenance delivery through a stand-alone clinic system detached from office-based medical practice.” [3]

Outside of the United States, however, buprenorphine was embraced: “By 1985, injectable buprenorphine had been marketed for analgesic applications in 29 countries and the sublingual tablet in 16 countries.” [3] In the U.S., the National Institute on Drug Abuse (NIDA) established its Medications Development Division in 1990, which approached Reckitts “about formalizing their already existing mutual interest in developing buprenorphine for addiction treatment. NIDA was interested in buprenorphine by itself and in combination with naloxone (to prevent diversion).”

Diversion “is defined as the unlawful channelling of regulated pharmaceuticals from legal sources to the illicit marketplace. This includes transferring drugs to people they were not prescribed for.” [6] Because of buprenorphine diversion in France, the drug had been classified as a controlled substance there, and prescriptions had fallen off; Reckitts saw a financial opportunity in the U.S. market and began to bring its focus to bear on the development of two products: Subutex and Suboxone, which were classified as drugs that would not recoup their development costs unless protected from competition by any generic equivalents for at least seven years. [3]

At the same time, Reckitts lobbied for the passage of the Drug Addiction Treatment Act of 2000, which allowed the U.S. Department of Health and Human Services to permit “qualified physicians to obtain a waiver from the separate registration requirements of the Narcotic Addict Treatment Act to treat opioid addiction” [7] with Schedule III drugs, among others — which was the category of controlled substance that buprenorphine was labelled upon its Food and Drug Administration approval in 2002.

Since that time, buprenorphine’s ties to the federal government’s oversight and encouragement of Medication Assisted Treatment (M.A.T.) have only strengthened the idea that buprenorphine is “considered the gold standard for treating opioid and heroin addiction.” [8]

How Does Buprenorphine Work?

buprenorphineBecause of its unique formulation, “buprenorphine is often the preferred option as an opioid replacement because it is a partial opioid agonist, meaning that it only partially stimulates the opioid receptors, causing a ‘ceiling effect’ that makes it much more difficult to overdose on compared to other opioid drugs,” according to Harvard Health Publishing [9], a division of Harvard Medical School. It “works by tightly binding to the same receptors in the brain as other opiates, such as heroin, morphine, and oxycodone. By doing so, it blunts intoxication with these other drugs, it prevents cravings, and it allows many people to transition back from a life of addiction to a life of relative normalcy and safety.”

Because of its role as a partial agonist — as well as the combination of buprenorphine with naloxone (the overdose reversal drug that is the active ingredient in Narcan) — buprenorphine has become “fashionable” in M.A.T. circles, because it’s seemed as a safer alternative to methadone, a full agonist that while blocking the effects of other opioids, still produces full opioid-like effects on its own. According to the nonprofit HIV information center TargetHIV.org [10], “Effects from a partial opioid agonist are weaker than those produced by a full opioid agonist, because they do not fully activate the brain's opioid receptors. Buprenorphine also blocks the effects of other opioids.”

Naloxone is added to discourage the abuse and diversion of Suboxone as an injectable drug. It’s poorly absorbed when taken sublingually, as most Suboxone strips are prescribed, but when injected (or sprayed nasally), naloxone “causes the immediate onset of withdrawal symptoms.” However, there are complications and concerns about Suboxone in the addiction treatment field.

“The harm reduction model doesn’t really apply to the level folks like to suggest it does,” says Travis Pyle, director of medical services at Cornerstone of Recovery. “It can be abused, and it is heavily abused in our community. Folks think you can’t use other opiates with it, but that’s just not true — you can override it, and the naloxone in Suboxone is short-lived. You’re not supposed to be able to use other opiates for 2 to 12 hours after you take it, but if you’re slamming a lot of other opiates, you can get past it.”

And at a certain point, opioid toxicity becomes a very real danger for individuals who are using buprenorphine in conjunction with other opiates: According to a 2018 report from the Maryville (Tennessee) Daily Times newspaper [11], Knox County Medical Examiner Dr. Darinka Mileusnic-Polchan and her colleagues found that Suboxone “increasingly is found at the scenes of overdose victims and in toxicology reports … she said since (2017), it increasingly has been common for investigators from the Regional Forensic Center to discover buprenorphine in toxicology tests of overdose victims, and also to find physical evidence of Suboxone use at the scene.”

While those incidents cast a shadow on buprenorphine’s role in addiction treatment, it’s important to note that it does have a place at the table, according to Dr. Fred “Kip” Wenger, medical director at Cornerstone of Recovery. However, he added, it’s often seen as a “magic bullet,” and without the behavioral health components necessary for sustained and effective addiction recovery, it is the very definition of substituting one drug for another.

“When it comes to harm reduction, it makes sense if done correctly, but there’s a lot of places that don’t do it correctly,” Wenger says. “A lot of those places become an exchange program — you give me money, here’s a prescription, see you later. Now, that’s better than sticking a needle in your arm, but is it ideal? No.

“I keep going back to my work in emergency medicine, which is transactional. If you break your ankle and come in to the ER, I make a diagnosis, order an X-ray, treat the break, say goodbye. But in addiction medicine, there’s an opportunity for something different — something transformational, if you will. If somebody is coming in who’s in full (opioid) withdrawal, throwing up in buckets and in an incredible amount of pain, we can try to treat the patient’s symptoms with fluids, Promethazine (an anti-nausea drug) and with Clonidine (a sedative and anti-hypertensive drug).

“But with Suboxone, you can literally stop the withdrawal and have a conversation with them and realize the person you’re talking to is a real person with real issues and real problems who doesn’t want to be in this situation,” he adds. “Suddenly, it becomes us not holding a club over your head while you’re puking in a bucket. It’s a wonderful bridge to the next step, which is to be determined.”

Buprenorphine: Pros

One of the biggest benefits of buprenorphine treatment for addiction is the availability of it to those in need of it for maintenance therapy, according to the Substance Abuse and Mental Health Services Administration (SAMHSA) [12]: “Unlike methadone treatment, which must be performed in a highly structured clinic, buprenorphine is the first medication to treat opioid dependency that is permitted to be prescribed or dispensed in physician offices, significantly increasing treatment access. Under the Drug Addiction Treatment Act of 2000 (DATA 2000), qualified U.S. physicians, and mid-level practitioners with an X-license can offer buprenorphine for opioid dependency in various settings, including in an office (physicians only), community hospital, health department, or correctional facility (mid-level practitioners).”

But it’s also found a beneficial role in residential addiction treatment settings like Cornerstone of Recovery, where it’s used during the Medical Detox phase of treatment and has made a world of difference for patients going through withdrawal for opioids.

“It has been a real blessing, because buprenorphine does help people who are addicted to opiates to not experience so much discomfort and all the physiological problems that go along with withdrawal from opiates without it,” says Dr. Scott Anderson, clinical director at Cornerstone of Recovery. “Prior to it, we only had more palliative types of medications, like muscle relaxers and over-the-counter medications like Tylenol, and they were just medications to treat the symptoms — but the person was still going through pretty significant withdrawals.

“With buprenorphine, you have a lot better chance of getting somebody through the withdrawal phase without them cutting their detox short and going back to drug use because it’s just too painful or uncomfortable. Opiate addicts going through withdrawal are hypersensitive to pain, so it’s very difficult to withdraw from opiates cold turkey, and buprenorphine has really helped with that. That it helps them get through the withdrawal process with a lot less discomfort helps them to stick with it and get on the road to recovery, and that has been a real plus.”

Science backs up the benefits of buprenorphine in  the detox process: One study by the National Drug Abuse Clinical Trials Network [13] that compared a buprenorphine taper to detox with clonidine only found that in an inpatient setting, 77 percent more patients assigned buprenorphine completed the detox and provided opioid-negative urine samples. In an outpatient setting, the results were similar — completion rates and negative urine samples were “much lower” for those who were given clonidine.

But what about buprenorphine maintenance treatment (BMT)? According to the National Institute of Justice [14], “The goals of BMT are to alleviate withdrawal symptoms, suppress opiate effects and cravings, and decrease the risk of overdose as a result of the illicit use of opioids.” BMT is generally broken down into three stages: induction (during which “patients are medically monitored”); stabilization (during which patients “no longer have cravings and experience few or no side effects,” and during which time “the dosage may also be adjusted”); and maintenance, which begins when patients are on a steady dose of buprenorphine: “The length of time that patients continue to receive BMT varies by individual and may be indefinite.”

Some of the benefits of BMT over methadone maintenance treatment:

  • Because buprenorphine is only a partial agonist, its effects on opioid receptors is weaker.
  • At “moderate doses, the effects reach a plateau and no longer continue to grow (known as the ceiling effect). Because there is no ceiling to the level of effects that methadone can induce, illicit drug use can lead to fatal overdoses.” Thus, some experts believe, buprenorphine “carries a lower risk of abuse, overdose, and side effects than do full opioid agonists.”
  • While methadone requires a daily dose, buprenorphine can be taken once every two days, because “although the effects … are not as strong as methadone, they last longer.”
  • Finally, “buprenorphine can be dispensed in office-based settings,” meaning that physicians with a special government waiver can prescribe it.

Is it effective? Yes, under certain conditions. A 2014 study [15] found that higher doses of BMT led to greater program retention and lower rates of illicit drug use by participants. And a 2018 roundup of various buprenorphine studies [16] found that:

  • “Patients in a Swedish treatment program randomized to buprenorphine had 1-year retention of 75% and negative urine drug tests in 75% of patients compared to 0% of patients randomized to placebo.”
  • In another study of 110 patients, “those who remained on buprenorphine after 18 months were more likely to be sober, employed, and involved in 12-step groups.”
  • In another analysis of data, BMT “was found to be superior to detoxification alone in terms of treatment retention, adverse outcomes, and relapse rates.”
  • Patients on buprenorphine “had reduced rates of HIV and hepatitis C transmission compared to abstinence-based therapy or detoxification alone.”
  • “Patients are safe to drive while on maintenance doses, and cognitive function in patients on buprenorphine maintenance is likely improved compared to other opioid users.”

Buprenorphine: Cons

buprenorphineAs with any medication, there are potential side effects that come with using buprenorphine as part of an M.A.T. regimen. According to Drugs.com [17], “Commonly reported side effects of buprenorphine include: constipation, dizziness, drowsiness, headache, and nausea. Other side effects include: drug withdrawal, fatigue, vomiting” and more. Long-term use of Suboxone for M.A.T. maintenance treatment brings with it a whole host of problems associated with long-term use of opioids — including anxiety, depression, physical distress to major organs (specifically the kidneys and liver) and gastrointestinal distress. However, the effects of long-term Suboxone maintenance on quality of life was an issue raised by Dr. Steven Scanlan in the publication Addiction Professional [18] a decade ago: “Supporters of maintenance treatment will state that the manageability of an addict's life improves tremendously with Suboxone maintenance, and there is an abundance of research to back this up,” he wrote in 2010. “Nonetheless, I believe that an individual on maintenance treatment is not experiencing the full range of emotions, good or bad.”

Three years later, research by a group of researchers published in the peer-reviewed journal PLOS One [19] addressed those same concerns, and the findings were concerning: In a study of 36 long-term Suboxone clients, they found that their emotional reactivity was “significantly flat,” indicating those clients had “less self-awareness of being happy, sad, and anxious compared to” control groups. “This motivates a concern that long-term (Suboxone) patients due to a diminished ability to perceive ‘reward’ … including emotional loss may misuse psychoactive drugs, including opioids, during their recovery process.”

And because buprenorphine is in itself an opioid, albeit only a partial agonist, there is abuse potential. As a joint reporting effort between National Public Radio and Kaiser Health News notes [20], “some people misuse it — they snort or inject the medication. And patients who have prescriptions for buprenorphine sometimes sell or give it away, which is known as diversion. Some policymakers and officials point to diversion as a reason to further increase regulations. Providers already need to be certified to prescribe it, and there’s a cap on the number of patients they can treat with the drug.” But, the report rationalizes, “a black market exists in part … because addiction treatment can be hard to find.”

A 2011 study published in the Journal of Addiction Medicine [21] corroborates that assessment to some degree: A survey among 100 opioid users found that 76 percent of them “reported having obtained buprenorphine/naloxone illicitly, with 41% having done so in the previous month,” and “the majority of participants who had used buprenorphine/naloxone reported doing so to treat opioid withdrawal symptoms (74%) or to stop using other opioids (66%) or because they could not afford drug treatment.”

But that’s not always the case. A 2013 report by The New York Times revealed a number of problematic areas with Suboxone’s role in addiction — including the 2010 death of a 20-year-old man whose friend was sentenced to 71 months in prison for giving him the buprenorphine that killed him.

“I didn’t know you could overdose on Suboxone,” Shawn Verrill told the Times [22] from the prison where he’s doing his time. “We were just a bunch of friends getting high and hanging out, doing what 20-year-olds do. Then we went to sleep, and Miles never woke up.”

The in-depth report goes on to detail how buprenorphine had given rise to a “volatile subculture” that included underground markets, recreational users and as a substitute for heroin in jails and prisons: “Buprenorphine has become both medication and dope: a treatment with considerable successes and also failures, as well as a street and prison drug bedeviling local authorities. It has attracted unscrupulous doctors and caused more health complications and deaths than its advocates acknowledge. It has also become a lucrative commodity, creating moneymaking opportunities — for manufacturers, doctors, drug dealers and even patients — that have undermined a public health innovation meant for social good.”

Buprenorphine’s role as “prison heroin,” physician and public speaker Kevin Pho’s website points out [23], led to the discontinuation of Suboxone strips by the Maryland Medcaid program because the “amount of diversion” to “jails and prisons” was “staggering.” The Wisconsin Sheriff’s Association asked for a discontinuation in 2017 because of a similar problem. And in Tennessee, Nashville Public Radio reported [24] that Dr. Richard Soper — the chief of addiction medicine at the Center for Behavioral Wellness in Nashville — “found that once the state’s Medicaid program moved to a newer (form of buprenorphine), which is supposed to be even less abusable, the number of statewide prescriptions for opioid addiction was cut by more than 60 percent.”

buprenorphineSoper went on to admit that he, like many other physicians who felt that Suboxone has indeed become the “gold standard” of addiction medicine, was caught off-guard: ““I thought when Suboxone first came out that that was pretty much going to be fool-proof.”

It’s something Anderson has seen regularly in his almost three decades in the field. In fact, when a new medicine is introduced, he almost always greets it with skepticism, he says, “because the addiction treatment field has a long history of introducing a drug that’s going to cure addiction, but what usually happens is that we get drugs touted as being non-addictive, only to find out down the road that oh, that was incorrect, they are addictive after all.”

“When it comes to the introduction of the latest and greatest, almost without fail these types of medications are heavily marketed, the positives are over emphasized, and the negatives or cons of them are underemphasized or ignored, or certainly underreported,” he adds. “Most of the published articles are going to be favorable about using buprenorphine — however, you really have to look at the details of the studies, the length of time being studied, the actual differences being demonstrated in the results, etc.  Often, the summaries of the articles lead a person to believe that the results are much more definitive than is actually the case.”

And in the case of buprenorphine, it backfired in a very public way: Earlier this summer, according to the news organization Reuters [25], Suboxone’s parent company agreed “to pay $600 million and have a subsidiary plead guilty to a felony charge to resolve U.S. allegations that it engaged in an illegal scheme to boost prescriptions of its opioid addiction treatment Suboxone.” Reckitt, the parent company of Indivior, was indicted in 2019 on charges that the company “deceived doctors and healthcare benefit programs into believing the film version of Suboxone, which has an opioid component, was safer and less susceptible to abuse than similar drugs. The indictment said Indivior also used an internet and telephone program touted as a resource for opioid addicts to connect them to doctors it knew were prescribing Suboxone and other opioids at high rates and in suspect circumstances.”

It’s ironic, in a sense, that the same federal government that sued a buprenorphine manufacturer continues to push it as the “gold standard” for addiction treatment. A 2016 piece in the online news organization Daily Progress [26] noted that “while federal funding for drug courts requires localities to offer Suboxone in their treatment programs,” “recovering addicts, elected officials and law enforcement agents throughout the mountain towns near the southwestern tip of Virginia say the drug is more menace than miracle. It's the most-abused, most-sought-after street drug across this region, which has been flooded with the drug like nowhere else in the state.”

That is not to say that buprenorphine should be off the table when it comes to Medication Assisted Treatment — on the contrary, abstinence advocates do not claim nor push the idea that buprenorphine is inherently harmful. Wenger, with three decades under his belt in emergency medicine in addition to his role as Cornerstone’s medial director, puts it plainly:

“Let’s be honest — abstinence is a really hard road, and not everybody can do it,” he says. “If I have a daughter or son who gets clean, loses their tolerance, relapses and is more susceptible to a deadly overdose — and does that over and over again — I would rather see them at a good Suboxone clinic that offers more than just handing out pills than try to get abstinence and fail and die of an overdose.”

But should long-term M.A.T. be the first tool that addiction medicine uses? If recovery is the goal, and abstinence-based recovery without the need for a maintenance medication is a viable path, then wouldn’t it make sense to try abstinence-based recovery first? Yes, writes Dr. Constance Scharff, an addiction and recovery advocate and speaker: “Recovery should be about breaking free from all substances that demand that a person consume them on a regular basis, whenever possible,” she wrote in 2016 [27]. “If your loved one genuinely wants a new life, start fresh, free from any kind of addiction. Suboxone and other MAT therapies are more appropriate for those who have shown themselves to be resistant to treatment, not as a first line tool in our addiction treatment arsenal.”

And if it is used as a first-line tool, Anderson believes it should look like what Cornerstone does: Employed in the detox process to help those addicted to opioids avoid the agony of withdrawal through a short-term taper that cleanses the system and allows them the clarity and physical well-being to grasp the therapies and concepts of both traditional and evidence-based addiction recovery.

“What’s happened over time with buprenorphine is that originally it was touted as more of a short-term aid to people trying to get past to opiate addiction and getting into recovery, but now it’s come to be seen as a long-term solution to addiction, and opiate addiction in particular,” Anderson says. “There’s been a movement to keep people on higher doses for an extended period of time, if not indefinitely. Over time, there’s even been a movement to loosen prescription regulations, despite evidence of diversion in the addict community.

“Despite the statement that you can’t get high off of buprenorphine, the truth is that you can. It’s not as primo a high as you would get from heroin or pure opiates, but if you use enough of anything, it’s going to impact you. You’ll get some degree of the feeling that you want, and in some cases, it’s also used as a way to cycle on and off of an addict’s drug of choice. They use it as a substitute to lower their tolerance, so they can go back to their drug of choice and use less to get high.

“That’s common knowledge within the addicted community, and we can’t just ignore that,” he adds. “It’s a significant problem, because you’re essentially handing people a drug that they continue to abuse, which continues to foster addiction.”

SOURCES

[1]: https://www.drugs.com/buprenorphine.html

[2]: https://www.acepnow.com/article/a-quick-guide-to-buprenorphine-products/?singlepage=1

[3]: https://www.researchgate.net/publication/221758758_Campbell_ND_Lovell_AM_The_history_of_the_development_of_buprenorphine_as_an_addiction_therapeutic_Ann_N_Y_Acad_Sci_1248_124-139

[4]: https://www.workithealth.com/blog/subutex-suboxone-buprenorphine/

[5]: https://jamanetwork.com/journals/jamapsychiatry/article-abstract/491905

[6]: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4657309/

[7]: https://web.archive.org/web/20130304203025/http://buprenorphine.samhsa.gov/titlexxxv.html

[8]: https://www.centerforhealthjournalism.org/2019/04/03/why-do-we-make-it-so-hard-prescribe-gold-standard-treating-opioid-addiction

[9]: https://www.health.harvard.edu/mind-and-mood/treating-opiate-addiction-part-i-detoxification-and-maintenance

[10]: https://targethiv.org/ihip/module-7-buprenorphine-know-facts#:~:text=Buprenorphine%20works%20in%20two%20ways,strong%20cravings%20for%20other%20opioids.

[11]: https://www.thedailytimes.com/news/opioid-addiction-medication-found-increasingly-in-overdoses/article_0d504ceb-7adc-5a7f-b06c-42b8b573f4d6.html/

[12]: https://www.samhsa.gov/medication-assisted-treatment/treatment/buprenorphine

[13]: https://www.drugabuse.gov/sites/default/files/BupDetox_Factsheet.pdf

[14]: https://crimesolutions.ojp.gov/practicedetails?ID=94#pd

[15]: https://pubmed.ncbi.nlm.nih.gov/24500948/

[16]: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5855417/

[17]: https://www.drugs.com/sfx/buprenorphine-side-effects.html

[18]: https://www.psychcongress.com/article/suboxone-concerns-behind-miracle

[19]: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3706486/

[20]: https://khn.org/news/black-market-for-suboxone-gives-some-a-glimpse-of-recovery/

[21]: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3157053/

[22]: https://www.nytimes.com/2013/11/17/health/in-demand-in-clinics-and-on-the-street-bupe-can-be-savior-or-menace.html

[23]: https://www.kevinmd.com/blog/2018/07/the-other-side-of-suboxone.html

[24]: https://wpln.org/post/tenncare-cut-coverage-for-suboxone-a-nashville-doctor-says-aftermath-shows-it-was-being-abused/#stream/0

[25]: https://www.reuters.com/article/us-usa-indivior-settlement/indivior-to-resolve-u-s-opioid-treatment-marketing-claims-for-600-million-idUSKCN24P1W5

[26]: https://dailyprogress.com/townnews/medicine/suboxone-helping-addicts-or-part-of-the-problem/article_87701211-254f-5472-9c23-b5aab465f168.html

[27]: https://www.psychologytoday.com/us/blog/ending-addiction-good/201607/three-reasons-reconsider-medication-assisted-treatment