In the lucrative but hit-and-miss opioid use disorder treatment field, buprenorphine is one medication that has demonstrated outstanding efficacy. It’s unfortunate that recent developments, by shining a critical light on the company that markets Suboxone, the best-known buprenorphine brand, will inevitably taint the medication itself in some eyes.
The Substance Use Disorders Institute (SUDI) of the University of the Sciences in Philadelphia is sufficiently concerned about this prospect to have issued the following statement on April 10:
The Department of Justice is pursuing criminal charges against one prominent manufacturer of buprenorphine (trade name Suboxone), an addiction treatment medicine. However, this is not an indictment of opioid use disorder medications and we are concerned that the grand jury charges announced on April 9 will be misunderstood. To be clear: misuse or diversion of buprenorphine prescribed in community settings is NOT the larger public health problem; opioid use disorder, overdose mortality, and a lack of treatment options are.
Suboxone was created with the help of Reckitt Benckiser Pharmaceuticals (RBP), the British Pharma giant; Indivior, a division of RBP which spun off fully in 2014, now markets the sublingual film version of the drug as well as an injectable version. Indivior’s quest to preserve its market share hit a brick wall on April 9, when a grand jury indicted it for fraud, among other things
Some background: First, there was only Suboxone, a combination of buprenorphine and naloxone which the US taxpayer paid to develop. The company sponsoring it was RBP. Suboxone was approved in the US to treat opioid use disorder (OUD) in 2002. As soon as a generic version was approved, Indivior, to retain market share, pulled its tablets from the market, citing pediatric exposures, and transferred patients to the newer, patented, film version. This all happened in 2011 and 2012, and is well documented in the indictment.
Nobody likes a Pharma company to protect its money-making turf by keeping out generics, but it’s not exactly unheard of.
There is now, finally, a generic form of buprenorphine-naloxone film available. Indian Pharma company Dr. Reddy’s has been trying to get this into the US market for a few years but was stymied by Indivior, which makes the Suboxone brand of the film. But Dr. Reddy’s film is now available and competitive.
Nobody likes a pharmaceutical company to protect its money-making turf by keeping out generics, but it’s not exactly unheard of. Still, in an era of an opioid-involved overdose crisis, and the outcry was mounting. It reached fever pitch with this indictment—more are likely to follow—and Indivior stock crashed after the indictment was made public.
“Policies around pharmaceutical marketing and patent exclusivity demand discussion too, and changes may be needed to deter abuses,” noted the SUDI. “We support increased competition in the addiction and overdose prevention medication space and lower costs for patients.”
Whether the different buprenorphine-naloxone formulations (tablet, film, injectable, generics vs. brand) are interchangeable is a clinical question, but also a practical one, because some are more affordable than others.
Filter obtained a full list of US buprenorphine prices from Elsevier, a global information and analytics company, which can be viewed here.
Indivior Fights Back, Citing Stigma
“Patients need a lot of options,” an Indivior spokesperson told Filter days after the indictment was announced. “The feedback that we’re getting from key opinion leaders and from ASAM [the American Society of Addiction Medicine] is that there is still so much stigma around the disease, and around being on medications. If we could break through that, it would be huge. What really has to happen is for treatment to be medicalized.”
Indivior is not fighting on behalf of its products alone, the spokesperson said—methadone and naltrexone are also approved to treat OUD. “We do everything within the regulatory and compliance guidelines to promote our products.” However, they argued, what is really needed is more overall access to buprenorphine and other approved medications: “Imagine what it would be like if all physicians had that waiver.”
The spokesperson was referring to the waiver needed to prescribe buprenorphine for OUD, which only around 5 percent of US physicians currently hold. Some advocates have been fighting the waiver, and the buprenorphine patient cap (30 for the first year, moving up to 100 and then 275 with further training and monitoring).
Indivior additionally attributes problems with uptake of Sublocade, its patented buprenorphine injection, to reimbursement issues. Indeed, why should a patient switch from a product that is working—and covered by insurance—to one that will cost more than $1,500 a month out-of-pocket?
Are Different Formulations Valuable? Or Just Lucrative?
Cynicism about Indivior’s tablet-film switch has abounded for years in the field. “I don’t think there’s a real difference between tablet and strip [film],” said Andrew Kolodny, MD, co-director of Opioid Policy Research at the Heller School for Social Policy and Management. “I think the strip was a gimmick intended for patent extension.”
His primary area of focus is the prescription opioid- and heroin-related crisis devastating families and communities. He is also the executive director of Physicians for Responsible Opioid Prescribing, and an arch-enemy of the opioid analgesic manufacturer Purdue, among others. But he is a strong supporter of buprenorphine as a medication for OUD—as are most in the field, given evidence of greatly reduced mortality among OUD patients who are prescribed it.
Kolodny told Filter that there is a challenge when switching between formulations. “Some formulations come in different doses, and sometimes even when the dose is supposed to be the same, I’ve had patients insist that one feels weaker than the other.”
Andrew Peterson, PharmD, PhD, executive director of USciences Substance Use Disorders Institute and a faculty member at Philadelphia College of Pharmacy, provided Filter with valuable information on variations between formulations, generic and branded.
Both tablet and film formulations are “safe and efficacious,” he said. “Patients tend to get used to the one they have been using, and can be reluctant to switch, especially if they are stable in their recovery.”
Different formulations of generic and branded buprenorphine-naloxone do have different patient preferences in terms of ease of use and taste, he said. In addition, the manufacturers do not offer the same doses for all formulations.
It’s also important to note that the most formulations of buprenorphine are to be dissolved in the mouth. Referred to as mucosal, buccal, or sublingual formulations, these forms of the medication—Suboxone and generic films, Zubsolv and Bunavail—have improved bioavailability over tablet formulations, because of the lack of “first-pass metabolism,” said Peterson. This means that the buprenorphine doesn’t have to go through the gastrointestinal tract first as occurs with oral, swallowed pills, but is absorbed directly into the bloodstream by dissolving in the mouth.
“Higher percentage of patients prefer faster dissolving of films or buccal formulations over tablets.”
“The choice of formulation for the physician and patient is often driven by which is covered on the patient’s insurance, which is often a function of price and contracting/rebating agreements,” noted Peterson.
He added that manufacturer-sponsored studies “found that higher percentage of patients prefer faster dissolving of films or buccal formulations over tablets. However, there have also been patients that didn’t like the way the film sticks to their teeth.” Some patients also reported mouth irritation with the film, and possible allergic responses to film-specific ingredients, he said.
In addition, sublingual tablets are soft by design, “and can sometimes break or crumble in the bottle,” said Peterson.
Some patients and physicians cut or split the medication for the correct dose. “Tablets could be cut or split, although not scored, and somewhat more difficult to split evenly, versus cutting film or buccal formulations with scissors,” said Peterson. He noted that splitting doses of either tablet or films is off-label—not tested in trials or described in the label approved by the FDA. However, this appears to be fairly common in practice. “Due to the buprenorphine’s long half-life, even if a divided dose is not exactly even, it’s not necessarily a concern, said Peterson.
Sublocade Waiting in the Wings
Indivior does have another patented buprenorphine product: Sublocade injection. Joshua D. Lee, MD, associate professor in the department of Public Health at NYU School of Medicine, said he believes Indivior “will recommend Sublocade to everyone, as that’s the new product they want to succeed long-term.”
Lee disclosed as a conflict that he recently received Indivior funding for a survey on buprenorphine and the criminal justice system led by Friends Research Institute, and is obtaining free Sublocade for a new NIDA-NYC jail pilot randomized controlled trial. But he told Filter that his personal guess is that the bulk of office-based OUD patients will prefer daily sublingual maintenance.
Still, “a lot more experience and a comparative analysis” is needed, he said. “The NYC jail pilot we are kicking off will directly compare sublingual bupe with Bup-XR [Sublocade] as persons leave NYC jails and continue maintenance in the community.”
Pharmaceutical companies like to play up the idea that some formulations have better “bioavailability” than others, or that some formulations are more likely to be diverted to the street than others. This is a common marketing differentiation tactic: Alkermes (maker of Vivitrol) used it against all of the buprenorphine brands, and marketers for Zubsolv, Bunavail and Probuphine (implant) used it against Suboxone.
One industry source told Filter that it’s pretty ironic if Suboxone is slammed for being divertable, as that would only help Sublocade sales.
This is also similar to Purdue pulling its old OxyContin off the market when its new “abuse deterrent” formulation came out.
How to Make Buprenorphine More Available?
Many people say the best way to ease access to buprenorphine is to remove the waiver requirement. “This is easy on the surface, but multiple stakeholders have a role to play, and this must be overcome,” said Steve Straubing, MD, medical director for a facility of Meridian Behavioral Healthcare, which has opioid treatment programs (OTPs) with methadone as well as buprenorphine/Vivitrol clinics in north central Florida.
Some states have requirements over and above what the federal government requires, such as a maximum allowable dose of buprenorphine absent conditions like a specialist consult. Some payers have specific requirements as well. “Here in Florida, Medicaid requires monthly updated treatment plans.”
Even if the waiver is removed, Straubing asked, “how do you convince providers to provide this treatment, and how do they get reimbursed?” Most current waivered providers see either no patients for buprenorphine, or are prescribing way below their cap, he said. He himself is waivered for 275 patients but has fewer than 100 (“maybe 95”) because he doesn’t have the ancillary staff to meet Florida’s Medicaid requirements, check vitals, count pills, check the prescription drug monitoring program, and so on.
“For a primary care provider to do this can be a real burden,” he said. “But if these things aren’t done, it will not only raise the ire of DEA folks, but has the potential for turning into another Wild West pill mill situation.” (Florida had buprenorphine pill mills galore, attracting people from other states, until the DEA shut them down.) “I guarantee there will be unscrupulous providers who will capitalize on a laissez-faire system,” said Straubing. “So how to increase access while providing quality addiction treatment services can be challenging.”
Straubing doesn’t think there’s much of a difference between Suboxone films and generic buprenorphine-naloxone tablets. “There may be some quality issues with some generics as far as dissolution of the product, but I don’t think it’s very significant and I believe that generics must show the FDA bioavailability data for their product.”
Something that isn’t even discussed in this formulation mix is straight buprenorphine—without naloxone, which, by negating the opioid experience, is what theoretically makes the product less liable to be used non-medically. Dr. Straubing isn’t sold on the idea that combining the buprenorphine with naloxone—something Indivior got paid by the federal government to develop, and something Indivior held onto for years after its patent expired, not sharing it with possible generics even in the midst of the crisis—is even necessary. Straight buprenorphine tablets (Indivior sells them as Subutex) are much less expensive than film.
Even the patients are cynical, though, about Indivior’s marketing. “There has been serious fallout from Indivior’s (or Reckitt’s) original argument [that naloxone needed to be combined to deter misuse], and it has serious clinical implications for a lot of patients including most of mine,” said Straubing. “The DEA is apparently pressuring pharmacies to refuse dispensing of plain cheaper buprenorphine except for pregnant women and documented allergies to films.” (Pregnant women should not take buprenorphine-naloxone, but rather the mono-product with buprenorphine only.)
While Straubing concedes that there is probably more diversion of the mono-product than the combination product, he believes this is probably a function of economics for the dealer. “If I can buy a mono tab for $3 retail and sell it on the street for $20, as opposed to $7.50 for a film with the same street value, it’s pretty obvious what I would do.”
Don’t Throw the Baby Out With the Bathwater
“The worry that I have with this indictment is that the general public and policy makers will throw out the baby with the bathwater,” said Leo Beletsky, associate professor of law and health sciences at Northeastern University School of Law, where he is also faculty director of the Health in Justice Action Lab.
“We have a big issue right now with insulin and epinephrine where pharmaceutical companies are engaging in all kinds of machinations to keep the price high,” he told Filter.
“This is not an indictment of the medication, but of the pharmaceutical industry.”
Buprenorphine is in fact under-prescribed, and should be more widely available, he said. That Indivior was trying to preserve profit-making activities is one thing. But when medications are facing the end of their patent exclusivity and manufacturers come up with claims to “evergreen” them, those claims deserve an extra level of scrutiny, by the FDA and everyone else, said Beletsky.
The indictment against Indivior and RBP is more an indictment about the companies’ “efforts to preserve their monopoly” than anything else, he said.
The entire brouhaha surrounding buprenorphine waivers, caps, and formulations could be avoided by more wholehearted support of opioid treatment programs and methadone.
And what about methadone? One thing is clear: the current administration, like previous ones, is supporting Indivior against other medications, including methadone.
The entire brouhaha surrounding buprenorphine waivers, caps, and formulations could be avoided by more wholehearted support of opioid treatment programs (OTPs) and methadone, which is unabashedly generic, cheap, and effective.
Allegra Schorr, president of the Coalition of Medication-Assisted Treatment Providers and Advocates (COMPA), a New York membership organization of OTPs, and owner and vice president of West Midtown Medical Group, an OTP., blames this on stigma. After all, if you really want to treat an unlimited number of OUD patients, why not just open an OTP, where you can dispense any medication and there is no federal cap at all?
OTPs also offer comprehensive care. “We firmly believe that this is something that has proven efficacy, and is what we need to support,” Schorr told Filter. “Buprenorphine is right for some people, but not for others,” she said. “It’s a great medication.”
In her facility, as should be the case around the country, all three major OUD medications—methadone, buprenorphine and naltrexone—are fully available.
As the SUDI stated:
Opioid overdose deaths are reduced as much as 50 percent by buprenorphine and methadone treatment, but we still lack capacity and access for all modalities of life-saving treatment, with nearly 65 percent of addiction treatment providers not offering these evidence-based treatments. It is easier to get heroin on the street than to get buprenorphine or methadone treatment in most of the US. This is the public health emergency we face and it’s driven by the structural and systemic barriers, funding/reimbursement gaps, and stigma. The solution starts with immediate efforts to revise outdated DEA regulations that impede access to low-threshold treatment and harm reduction services.