Archive for the ‘Buprenorphine’ Category

Tapering Off Suboxone: Three Patients’ Success Stories

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

This year I’ve had three long-term patients taper off the buprenorphine products I was prescribing. All three are doing well and are happy with their treatment outcome. Since tapering off buprenorphine products can be challenging, I thought I’d share their stories, to help other people who wish to taper off buprenorphine. (Note that when I say buprenorphine, I mean to include all the brands and generics: Suboxone, Zubsolv, Bunavail, generic combination product buprenorphine/naloxone and the generic monoproduct buprenorphine.)

The first patient had been on buprenorphine for over ten years. She saw one of the first physicians to prescribe buprenorphine, and I inherited her from this prescriber after he retired.

When she started Suboxone, which at that time were only available in tablet form, she stabilized at eight milligrams. She stayed on that dose for about four years. She saw her prescriber monthly for the first year and a half, then every other month. By the time she started seeing me, she had cut her dose to 4mg per day without too much difficulty. When the suboxone films were available, we switched to those, both because that’s what her insurance would pay for and because I thought she could taper more easily with films.

Over the first year with me, she brought her dose down to 2mg per day, reducing by a half milligram every three or four months. I then switched her to the 2mg films, and she continued to cut off more and more from her films. I gave her some guidance, but she largely managed her taper on her own.

After a year or two, she asked me to prescribe only fifteen films per month, since she was taking half of a film per day. A year later, she had dropped to only a forth of a film per day, and needed only eight films per month. This slowly progressed until she had brought her dose down to one-sixteenth of a two milligram film which she took every other day.

That’s right…she was taking .125milligrams every other day. Her urine drug screen still showed positive for buprenorphine at her visits. I told her I thought she could stop taking that dose and not have any withdrawal symptoms, but she told me she still felt withdrawal if she missed her every other day dose. I didn’t push her; I didn’t mind prescribing only one 2milligram film per month!

She continued at this dose for over a year. When she missed a visit earlier this year, I asked my staff to call her. Sure enough, she forgot to take her dose for several days, and didn’t feel any withdrawal. I offered to see her one more time, to talk about relapse prevention and options to give her insurance against a relapse (Vivitrol), but she didn’t want another visit. I congratulated her and told her if she had questions or problems in the future to call us.

During her last year or so, we talked regularly about relapse prevention. We made plans for what to do if she had a catastrophic medical problem that required pain medication (broken bone, surgery, etc.). We discussed other big relapse triggers, such as strong negative emotions, and being around people who had opioids or other drugs.

This patient was very involved with 12-step recovery. Even after so many years of recovery, she went to three or more meetings per week. She had a sponsor and served as a sponsor to newer members. She had relatives in 12-step programs, and most of her friends were members of 12-step recovery groups.

The second patient also tapered her dose over years. I knew her for around fifteen years, first as a patient at an opioid treatment program, where she dosed on methadone. She did well from the start, though she had some slips with non-opioid illicit drugs.

She didn’t care for the restrictive nature of the opioid treatment program, so when she’d been doing well there for several years, I told her about the new option of buprenorphine treatment through an office setting. She decided that was what she wanted to do, and proceeded to taper her methadone dose, slowly.

Once she was down to 30mg, which took about six months, she made an appointment with an office-based physician, who started her at suboxone 16mg per day. When that physician retired less than a year after she started Suboxone, she transferred to my office-based program.

By the time she transferred to my office-based program, she was down to 12mg per day. Just like the first patient, she steadily tapered her own dose. She reduced her dose by an estimated milligram of Suboxone every four months.

I say estimated because cutting the Suboxone films is largely guesswork, and the manufacturer says there are no studies to show buprenorphine is evenly distributed over the film. While that’s true, buprenorphine is so long-acting that I wonder how much variation patients get in their blood levels, even with uneven distribution.

Just like with the first patient, we switched her to the 2mg film once she got to a 2mg per day dose. She continued to reduce on her own. She would cut her dose and wait for a month or two before going down again. I saw her only every two months, given her stability. She had negative drug screens, always kept her appointments, and lead a productive life. I gave her as much advice as I could, but I was impressed that she was able to listen to her body and taper only as fast as she was comfortable.

Once she was taking one-eighth of a 2 milligram film (.25mg), she stopped her medication. I saw her for one last planned visit, and we talked about how she felt. At that point, she’d been off buprenorphine for four weeks. She noticed aches and pains more intensely than in the past, but said it wasn’t anything ibuprofen or Tylenol couldn’t fix. It took a little longer to get to sleep, but she was still functioning well as a mother to her four children. She was ecstatic to be finished with medication-assisted treatment, and she knows that – heaven forbid – if she does relapse, to call quickly and come to see me to get back on buprenorphine.

Again, we had been discussing relapse triggers for months. We also discussed naltrexone, available as a once monthly shot called Vivitrol, as insurance against a relapse but she decided against it. She felt she didn’t need it.

She did individual counseling while she was a patient at the opioid treatment program, but hasn’t done much counseling recently. She saw a therapist many years ago, after a traumatic life event, but didn’t feel she needed to continue with this. She tried 12-step recovery but didn’t feel it was right for her.

Initially I worried she wouldn’t make progress in her recovery without continuing to see a therapist, but when I saw how well she was functioning in life, I decided not to push the issue. The only counseling she got was with me, during our 20-minute office visits. I’m not a trained therapist, but I like to think I have developed some skills over the years.

Her life changed completely over the past ten or so years she’s been on medication-assisted treatment. Early on, she let go of drug-using friends and acquaintances. She became focused on what was important to her: her young family and her extended family. She got a part-time job after her youngest child started school, to afford some extras for the family. Her husband is in his final stages of taper from buprenorphine, and she hasn’t rushed him, letting him take his own time, just like she did.

Drug use holds no allure for her; she hasn’t had any cravings or desires for any sort of drugs for years.

My third patient to taper off this year just saw me several weeks ago. It’s been over eight years since she used any illicit drugs. At her last visit, she declared this to be her last visit, saying her last buprenorphine had been taken six weeks prior, and that she felt fine.

She has been at a dose of less than 8mg for about two years, and less than 2mg per day for at least the last eight months. She tapered on the generic combination tablets, buprenorphine/naloxone 2/.5mg, cutting them into quarters. Once she got to one-quarter per day (.5mg), she took one of these quarters every other day for several weeks and then stopped completely.

Again, we’ve been discussing relapse prevention for literally years. Again, she decided against starting naltrexone as a safety net against relapse, feeling she didn’t need this medication. She was happy and smiling and was very kind when she thanked me for helping her these past years. I told her it was truly my pleasure, and I was honored to be even a small part of her success.

These three patients have common themes in their successes. All three had very support families who didn’t rush them to get off buprenorphine or shame them from being on it. I also didn’t pressure them. I said I’ll do everything I can do to help you taper off this medication, but there’s nothing wrong with staying on it either, if that’s what you prefer.

This left the decision in their hands. All three said this was important, since they had control over when/if/how they tapered. Once I told one of these patients to listen to her body, since she was the expert on her body and how it felt. This resonated with her, and she thanked me for saying that. She felt that took the pressure from her to try to meet someone else’s expectations.

These three patients all tapered their dose very gradually, over periods of not days or weeks, but months and years. While such slow tapers can be frustrating, not to mention expensive, to people who want a quicker exit off medication, maybe slow tapers allow the body more time to adjust to changes in dosage.

Two of the three patients exercise regularly at a gym. The third is also active, and walks nearly daily. Exercise usually helps us to feel better, both physically and emotionally. I wonder if exercise also boosts endorphin, our body’s own opioid. I’ve started recommended patients start a reasonable exercise program in advance of starting a dose taper.

All three of these patients have faced serious adversity in the past and survived it. This tells me they have skills they can use in their recovery. All three had tremendous resolve to do what was necessary to get their lives back. They kept at it, accepted the few setbacks that came their way as part of the process, and kept moving forward, even though progress was slow at times.

I admire all these patients. All have excellent prognosis, and we’ve talked about how opioid use disorder is a chronic illness. They need to be on guard against relapses the rest of their lives, and if relapse happens, I think they will know what to do.

I have another crop of patients who are dosing at 4mg or less of buprenorphine per day, all in the process of tapering. I’ll update my blog with those stories after they taper.

 

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Not Dying: A Worthy Goal

 

 

A new study about opioid overdose death and treatment of opioid use disorders was published in the Annals of Internal Medicine this month. [1]

It showed that people who experience a non-fatal overdose have a significantly reduced risk of death if they start on medication-assisted treatment with methadone or buprenorphine. Naltrexone was also examined but limited data prevented conclusions about the use of this medication.

This large cohort study, done in Massachusetts on adults age 18 and older, covered the four years from 2011 and 2015. Subjects were identified as people who experienced at least one non-fatal opioid overdose and survived at least for 30 days afterward. Patients were excluded if they had a diagnosis of cancer.

This turned out to be a huge study, with over seventeen thousand study subjects.

In the year prior to the overdose event, 26% had received at least one medication to treat opioid use disorder. Twenty-two percent received opioid detoxification at least once. Forty-one percent had received an opioid prescription in the preceding year, and 28% received a prescription for a benzodiazepine within the previous year.

For these same patient, in the year after their nonfatal overdose, 30% received at least one medication for opioid use disorder (13% got buprenorphine, 8% got methadone, and 4% got naltrexone. The other 5% received more than one medication.)

People younger than 45 were more likely to received treatment with medication, as were people with diagnoses of anxiety or depressive disorders.

In the year after overdose, 4.6 of the people with a prior non-fatal overdose died, and of those, 2.1% died from opioid-related causes.

For patients treated with medication for opioid use disorder, both the all-cause mortality and opioid mortality rates were significantly reduced; they were cut approximately in half.

Patients who started n methadone after their non-fatal overdose had markedly reduced risks for both all-cause mortality and opioid-related mortality, with the adjusted risk at around half what it was for untreated patients. Results for patients on buprenorphine were nearly the same; they had not quite the degree of risk reduction as with methadone, but still significantly lower risk of death than patients on no medications.

There were no associations between risk of death for patients started on naltrexone, but the authors noted this was a smaller group, so any differences weren’t statistically significant. Of note, most of those patients were only treated for a month or two.

So what does this study tell us?

We have another study that shows medication-assisted treatment with methadone or buprenorphine reduces the risk of death, this time in people with at least one prior non-fatal opioid overdose. In this study, being methadone or buprenorphine reduced deaths from all-cause mortality, as well as opioid-related mortality.

We also see, again, that only a minority of people, 30%, with nonfatal overdose were started on life-saving medication.

I was surprised the percent of people referred for medication-assisted treatment was that high. This study was done in Massachusetts, a state that’s probably at the forefront of opioid use disorder treatment. They have some excellent providers and physician leaders, and better methods to pay for treatment in that state.

I don’t think rural areas in North Carolina come close to a 30% referral rate. I’d be amazed if 2-3% were referred for evidence-based treatment with medication. I suspect most people here who survive near-fatal opioid overdoses aren’t directed, referred, or even informed about medication-assisted treatments. People get referred to OTPs around here by concerned friends and family members, but rarely by physicians.

It has started to change. In our area, of the three OB/GYN groups, we have one practice that refers patients to us. The LME (local management entity, which contracts with the state to see people on Medicaid and those with no insurance) has referred less than a handful of people for treatment. That’s a dramatic improvement from seven years ago when the LME told patients to get off methadone.

But back to the study. So even in one of the most progressive states, only 30% of people got life-saving treatment.

Let’s picture a patient who has a near-fatal episode of a different chronic disorder. Thankfully, the patient survives this episode. There’s a treatment medication for this disorder that will reduce the patient’s risk of dying by half over the next year. What do you think would happen if this patient wasn’t given or referred for that life-saving treatment?

There would be an outcry. There would be wringing of hands and rending of garments, and possibly gnashing of teeth. There would be lawyers…malpractice lawyers, swarms of them.

Yet this exact situation happens over and over, again and again, in emergency departments across this nation.

To be fair, this article doesn’t say why the patients who survived a near-fatal overdose weren’t started on medication. Maybe emergency department personnel offered this medication but the patients refused.

Realistically, there are significant barriers to starting medication-assisted treatment of opioid use disorder. Methadone can only lawfully be prescribed from a properly-licensed opioid treatment program. Maybe emergency department physicians gave referrals to OTPs, but the patients didn’t show up. Maybe they referred to office-based buprenorphine prescribers.

Every time I do an intake on a patient entering treatment with MAT, I ask if there’s been an overdose in their history. Much of the time, the answer if “Yes.” I then ask what kind of recommendation for treatment they got. Most times the patient looks at me blankly. They can’t think of any kind of treatment recommendation or referral. One patients said, “They told me to quit using drugs.”

Telling people to quit using drugs IS NOT treatment for opioid use disorder. It’s sad that I even have to write this, as it should be well-known by all medical personnel.

All of us working in this field need to keep chugging along. We need to put this article in our mental back pocket, ready to talk about if/when the time comes when we hear stale old beliefs about medication-assisted treatments.

This study points to the bottom line: “We are using medications that reduce the risk of dying by half, for people who have had a prior nonfatal overdose.” Not dying is a huge benefit of treatment, perhaps the ultimate benefit.

It is long past time for medical professionals to set aside their personal opinions and what they think they know, in favor of hard data. Methadone and buprenorphine reduce the risk of dying, and patients with opioid use disorder must be informed & encouraged about these treatments. To do otherwise is malpractice.

  1. Larochelle et al., “Medication for Opioid Use Disorder after Nonfatal Opioid Overdose and Association with Mortality: A Cohort Study,” Annals of Internal Medicine, June 19, 2018

The Blues

 

This letter was published in the Raleigh News & Observer last week, about insurance coverage for treatment of opioid use disorder. It was written by Alex Gertner, an MD/PhD student at University of Chapel Hill’s School of Medicine and the Gillings School of Global Public Health.

I know Alex from his participation in UNC’s Project Echo, a program designed to connect new providers of office-based buprenorphine treatment with more experienced providers, for assistance and support. The goal of UNC ECHO is to get more primary care physicians and physician extenders to prescribe buprenorphine, so that people wanting treatment can get it more easily.

 

The opioid overdose epidemic continues to devastate North Carolina communities, even though effective treatments for opioid addiction exist that allow individuals to lead healthy, fulfilling lives. During this crisis, you might think that North Carolina’s largest private insurer would be helping as many people into treatment as possible, but that is unfortunately not the case.

As a medical student researching the opioid epidemic, I spend time in addiction clinics and talk with addiction providers from across the state. A complaint I hear from these providers is that Blue Cross and Blue Shield is making it harder for their patients to access treatment.

Buprenorphine is the main drug used to treat opioid addiction in office-based settings, like primary care offices. BCBS requires providers to request prior authorization to start buprenorphine. These prior authorizations can require days of back-and-forth discussions until approval, during which time a person seeking treatment is at risk of overdose. Sometimes authorizations are denied even after appeals from providers.

Part of the reason for these denials are BCBS’s criteria for approval, which conflict with evidence and best practices. As the criteria state, BCBS may deny a person buprenorphine if that person is using illicit drugs. But illicit opioid use is a symptom of addiction. That is like denying someone insulin because they have high blood sugar. The American Society of Addiction Medicine says that the use of addictive drugs only should not be a reason to suspend opioid addiction treatment.

BCBS will also deny buprenorphine if its thinks someone isn’t following a “psychosocial treatment plan,” such as counseling. Unfortunately, many communities across the state don’t have addiction counselors who take insurance. What’s more, evidence shows that counseling helps some people who get buprenorphine, but not others. Even if someone would benefit from counseling but isn’t getting it, that doesn’t justify withholding a medication that could save their life.

Office-based buprenorphine treatment doesn’t work for everyone. Some people need more specialized clinics known as opioid treatment programs. I called several of these programs and was told that BCBS rarely pays for this type of treatment. One provider told me people with BCBS seeking care at opioid treatment programs are better off being uninsured, because then they could access public funds to pay for treatment. Imagine if, at the height of the AIDS epidemic, insurers didn’t cover treatment at specialty HIV clinics. Drug overdoses are now claiming more lives than HIV at the height of the AIDS epidemic.

There are other ways in which BCBS is making it harder to get treatment, such as denying certain dosage formulations or charging high cost-sharing. Such actions may appear minor, but every disruption in treatment can lead to a potentially deadly relapse.

In contrast to BCBS, North Carolina’s Medicaid program covers treatment at opioid treatment programs and stopped requiring prior authorizations for the most common formulations of buprenorphine.

I wrote to BCBS to share these concerns. It said it follows CDC and FDA criteria for approving treatment. In fact, no CDC or FDA criteria recommend withholding buprenorphine because of illicit drug use or lack of psychosocial support. Federal recommendations stress the importance of access to opioid treatment programs.

The reason why BCBS applies such strict criteria may lie in a different part of BCBS’s response: “The street value of these products are high and these medications are used by addicts to maintain functionality between abuse, thus perpetuating the epidemic. A similar rationale is used for why we place prior authorization on extended release opiates.” It is true that buprenorphine has a street value, but that’s largely because it’s so hard to find treatment. Research shows that illicit buprenorphine use is mainly driven by attempts to self-treat addiction.

The use of the term “addict” in BCBS’s response is also troubling. The Office of National Drug Policy has stated that terms like “addict” can negatively affect perceptions of people suffering from addiction.

BCBS should end prior authorizations for commonly prescribed formulations of buprenorphine, align its approval criteria with best practices, and start covering opioid treatment programs. The opioid overdose epidemic is the public health challenge of our generation. How and whether North Carolina will emerge from this epidemic will depend in large part on BCBS’s response.

Read more here: http://www.newsobserver.com/opinion/article212771774.html#storylink=cpy

When I compare Alex’s vision and concern for such important health issues, I can’t help but to think of my days as a medical student. My concerns were narrow; I only cared about getting through medical school and into a good residency. But Alex is already working on an issue that’s so important to this country.

As you can tell from Alex’s letter to the editor, he understands the issues and eloquently advocates for Blue Cross/Blue Shield to deliver better assistance for patients with opioid use disorder. After I read his letter, the only thing I can say is “Amen!” All of the issues he listed have happened to my patients.

I pray Alex decides to work in the field of Addiction Medicine. We need him.

Buprenorphine Regulations

Map is from vox.com

In response to the rise of opioid use disorders in this country, lawmakers in heavily affected states are passing laws they hope will help. But well-intentioned laws may have unintended consequences, requiring re-evaluation of those laws.

Nearly one year ago, The Virginia legislature asked the Virginia Board of Medicine to regulate prescribing of buprenorphine. Legislators were worried about the diversion of prescribed monoproduct buprenorphine to the streets. You can read about this in more detail in my blog entry dated February 24, 2017.

It’s been a year since that blog entry, and I have a little bit of data regarding some of the consequences of Virginia’s new rules.

Initially, the new Virginia Board of Medicine (VBOM) regulations said the buprenorphine monoproduct could only be prescribed for pregnant ladies and nursing mothers. They did this because the monoproduct, containing only buprenorphine and no naloxone, has a higher street value and is more likely to be injected and misused than the combination product.

The VBOM received so many complaint letters that they finally changed the regulations to say that each buprenorphine physician could prescribe buprenorphine monoproduct to up to three percent of their patients. Each of these patients must have documentation of their intolerance in their chart.

It was hoped that this compromise would limit the amount of buprenorphine monoproduct being prescribed, while still making allowances for some patents with intolerance to naloxone in the combination product.

The VBOM didn’t stop there. They passed regulations about care at opioid treatment programs (OTPs), which are already the most heavily regulated medical providers in the nation. The VBOM said if buprenorphine monoproduct was used, the patient had to consume it on site, with observed dosing, and that no take home doses could be allowed for the monoproduct.

To clarify, this meant that OTP patients dosing with buprenorphine monoproduct had to either switch to the combination product, buprenorphine/naloxone, to get their usual take homes, or dose daily at the OTP on the monoproduct and forfeit all the take homes they had earned.

Or they could switch to methadone, where take homes are still allowed, following standard guidelines.

This is the irony – methadone is a heavier and stronger opioid than buprenorphine, and more likely to cause overdose death if taken illicitly or diverted. Virginia patients can get methadone take home doses, after they have a period of stability and meet the guidelines which have been in place for decades.

OTPs must follow both state and federal guidelines, and must obey the stricter of the two. The federal guidelines dropped the time in treatment requirement for buprenorphine, meaning the federal agency decided to allow the admitting physician to decide how many take home doses were appropriate, from day one, for a buprenorphine patient.

Essentially, Virginia went the opposite direction, and eliminated take homes, at least for the monoproduct.

At the time the new regulations were implemented, there were 600 Virginia patients on buprenorphine at OTPs. Monoproduct was used because was about half the price of the combination product, and kept treatment more affordable for patients. Also, because OTPs already followed stricter regulations than office-based programs, the risk of diversion was felt to be lower than at office-based programs.

Of those 600 patients, 384 patients attended one of the four OTPs owned by Acadia Healthcare in Virginia. They collected data on what happened to their Virginia patients after these new regulations were implemented. Since I work for Acadia, that data was released to me for an upcoming presentation, but I’ll give my readers an early view.

Of those 384 patients, 260 made the switch to the combination product so that they could continue to get take home doses. In other words, two-thirds of the patients switched, and one-third did not.

The cost of medication doubled, but rather than pass this on to the patients, Acadia Healthcare absorbed all the extra cost. The patients paid the same as if they were getting the cheaper monoproduct. This was fortunate, since an overnight doubling of costs could have caused hundreds of patients to leave treatment.

To some lawmakers, an extra couple of hundred dollars per month might not seem like much. But to many patients, it’s the difference between being able to stay in treatment or having to leave and go back to illicit drug use.

So, what happened to the patients who didn’t make the switch?

  • 15 switched to methadone, and will be able to get take home doses once they meet criteria. It’s takes a while, but at least they can get take homes eventually.
  • 21 transferred to out-of-state opioid treatment programs because they had an intolerance to the combination product.
  • 24 (6%) patients dropped out of treatment.
  • 58 remained on the monoproduct and accepted that they will have to dose every single day that they are in treatment. Since all these clinics are in rural areas of Southwestern Virginia, I suspect some of these people are driving long distances daily, and incurring extra expenses for that travel.
  • 6 patients were lost to follow up, and couldn’t be contacted to see what happened.

Studies show the risk of death increases as much as eight-fold for patients who leave treatment, so those 24 people are at high risk. I suspect the 6 people who couldn’t be found are also in that risk group.

I have a little bit of data about what’s happened on the receiving end with patients on buprenorphine at Virginia OTPs. One OTP located in Boone, NC, received 12 patients in transfer from Virginia. Those patients could have been OTP patients or office-based patients; I don’t have that data.

I have my own office-based buprenorphine practice in the Lake Normal area of North Carolina, which is 73 miles from the North Carolina-Virginia border. My practice got around twenty phone calls last year, just after Virginia’s law changed. These patients were willing to drive from Virginia to my office if I would prescribe buprenorphine monoproduct. I declined to accept any of those patients, both because it is unworkable in the long run to come from such a distance, and because I was concerned about regulatory scrutiny in my own state.

You can draw your own conclusions based on this limited data. It appears that roughly two-thirds of patients, if forced to switch to the combination product, can do so and remain in treatment.

But remember, costs weren’t increased for those patients enrolled at Acadia OTPs.

That would not have been the case for office-based self-pay patients, who would have paid roughly double each month for their prescriptions for combo products at the pharmacy. Community pharmacies would not have absorbed the extra cost.

I combed the internet, trying to discover data on what happened to office-based patients in Virginia on the monoproduct. If data is out there, I haven’t found it. Or perhaps it’s still being collected and analyzed. I also looked to see if overdose death data changed much in 2017, but it’s likely too early for this.

The American Society of Addiction Medicine has written a public policy statement addressing regulations on office-based buprenorphine policy. This document outlines the most reasonable approach to assure appropriate care for patients while limiting onerous regulations for providers. State legislators would do well to read this policy and abide by its specific recommendations.

https://www.asam.org/docs/default-source/public-policy-statements/statement-on-regulation-of-obot.pdf?sfvrsn=df8540c2_2

I’m tempted to give a summary of ASAM’s statement, but ASAM warns against this, at least without their permission. They don’t want people to use just a section of their policy to justify a position; they want their statement to be read in full.

I think that’s smart of ASAM. I encourage interested readers to check it out.

Buprenorphine Monthly Injection: Sublocade

 

 

 

 

 

 

 

 

 

 

 

Late last year the FDA approved Sublocade, the brand name of a monthly buprenorphine injection, marketed by Indivior, the same company that sells Suboxone brand sublingual films. Sublocade is expected to be commercially available by February or March of this year.

This medication is indicated for patients with moderate to severe opioid use disorder who have stabilized on transmucosal buprenorphine products for at least seven days. Sublocade comes in a pre-filled syringe, and is injected into the subcutaneous tissue over the abdomen. This viscous liquid forms a solid deposit containing buprenorphine, and the medication is released over a month, giving therapeutic plasma levels of buprenorphine.

Thus far, we have two studies, one a randomized controlled trial and another that was an open-label study, that both show Sublocade, compared with placebo, was significantly more likely to result in fewer positive drug screens for illicit opioids and in fewer self-reports of illicit opioid use.

Of note, the manufacturer warns against attempts to inject this preparation intravenously, because the solid mass that forms can block a blood vessel, or travel in the vessel to the lungs, possibly causing death from a pulmonary embolus. To reduce the risk of this bad outcome, the medication will only be distributed to healthcare professionals, and not to patients.

Sublocade comes in two doses; a 300mg dose and 100mg dose. Patients should receive 300mg per month for the first two months, then drop to 100mg per month. This is the indicated dose for patients on the equivalent of sublingual buprenorphine 8 to 24mg per day. If patients have inadequate response after dropping to 100mg, the dose may be increased to 300mg in some patients, if the physician feels this is indicated. At the manufacturers website, they say Sublocade delivers a dose adequate to block opioid receptors to the degree that if other opioids are used, they will have no effect.

Steady state is established after 4-6 months of treatment. Steady state is a term describing the pharmacokinetic state where the drug’s intake is in dynamic equilibrium with the drug’s elimination from the body. Usually this occurs after four to five times the drug’s half-life. After steady-state has been achieved, buprenorphine may be detected in patients for up to 12 months after dosing stops. It is unknown how long buprenorphine will remain detectable in urine testing.

After this medication is stopped, the patient should be monitored for opioid withdrawal symptoms for several months, since blood levels will drop slowly.

Indivior recommend checking liver function tests at baseline, then monthly.

Because of the possible harm of intravenous use of this product, Indivior created a REMS (Risk Evaluation and Management Strategy) protocol. Healthcare settings seeking to dose Sublocade and pharmacies wishing to dispense Sublocade must be certified by the REMS program for this medication.

I tried to go to the website mentioned on the Indivior website regarding the REMS requirements, but the link wasn’t working for me.

I’m excited about this new option because it can reduce diversion of buprenorphine products. At the opioid treatment program, we have a fair number of patients who attempt to divert or misuse sublingual forms. At present, if I have unmistakable evidence a patient is trying to divert medication, I can no longer prescribe it. I can offer to switch the patient to methadone, but that’s unattractive for several reasons to many patients. But if we can administer subcutaneous buprenorphine, it gives us another option. It would be difficult to divert, and it isn’t as complicated to administer as the Probuphine implants.

I do have some concerns. First, how do the financial aspects work? Since it can only be dispensed to the healthcare provider for administration to the patient, I suspect the facility or physician owner of the practice will need to buy the medication and pay up front. What if a patient’s insurance company refuses to pay? What if a patient refuses to pay, or only pays part of the drug cost? Could the physician lose money treating patients if this happens?

Currently, with sublingual buprenorphine products, the physician isn’t in the middle. The patient pays the pharmacy directly.

I was thrilled to learn that North Carolina’s Medicaid program will pay for this medication, without even requiring a prior authorization. That’s wonderful, but many private buprenorphine practices don’t treat Medicaid patients, due to low reimbursement rates. But this will be good for facilities who do accept Medicaid as payment.

I’m amazed our state can afford this. Perhaps they got a much better deal from the drug company, Indivior, than the quoted priced of $1500 to $1800 per month. One month’s worth of generic monoproduct buprenorphine, dosed at 16mg per day, costs about $105 per month at the cheapest retail pharmacy, according to goodrx.com. That means this new subcutaneous injectable formulation costs fourteen times more than the cheapest form of buprenorphine on the market.

That’s quite a difference. I’m assuming the state’s willingness to pay this expense is based on expectation of a marked decrease in diversion of this medication. Apparently, the lump of buprenorphine can be cut out if it’s done within the first 14 days, but that seems an unlikely extreme for patients. In other words, with the monthly injection, the medication will reach the patient for whom it is prescribed.

At this point we could launch into a discussion about whether diversion of buprenorphine – possibly the safest opioid available – is a good or bad thing. Law enforcement types see diversion as bad, but arguing a pure harm reduction viewpoint, one could say that diverted, black market buprenorphine might be saving lives by giving people with untreated opioid use disorder a safer option. Note that I said safer, not safe. But that whole debate is an entire blog post so I’ll keep the focus on this new way of delivering buprenorphine.

About half of my office-based patients are self-pay, with no Medicaid or private insurance. They pay out of their own pocket for my office charges, and pay for their medication at their pharmacy. I think Sublocade’s price will make it an unworkable alternative for these people. About half my patient have private insurance, and most have Blue Cross/Blue Shield. I plan to make some phone calls, to get information about their payment policy for Sublocade.

I’m eager to try this new preparation at the opioid treatment program. It sounds like this will be workable for Medicaid patients.

But that brings up my second concern: how can I get patients to come for weekly counseling sessions if they only get medication once per month? I was pondering this idea in a group Email yesterday when I was informed (by someone who knows these things) that soon, a competitor of Indivior will be releasing a weekly injection form of buprenorphine. He envisioned weekly injections for new patients, with gradual decreasing of frequency of visits as the patient stabilizes, eventually moving to monthly treatment and counseling sessions, when clinically appropriate.

I like this idea. This sounds workable. And as I emailed him…let’s hope there’s a price war, with both companies lowering their prices to attract patients.

I’m happy about any new options for patients, and I’m eager to use this product. I just hope cost won’t be a deal-breaker for patients and their insurers.

 

Subcutaneous Buprenorphine Injections for Treatment of Opioid Use Disorders

 

 

 

 

 

I’ve blogged in the past about studies conducted on CAM2038, a new preparation of buprenorphine that can be given in a subcutaneous injection weekly or monthly. I think this delivery system holds great promise for the treatment of opioid use disorder.

Earlier this year, pharmacokinetic data from healthy volunteers showed that blood levels with the subcutaneous injections equaled the levels provided by sublingual means. This data supports the idea that the injections should provide therapeutic levels in patients with opioid use disorder. [1]

Later this year, a Phase II study was published in JAMA Psychiatry. Weekly subcutaneous preparation of buprenorphine was administered to 47 subjects with opioid use disorder. These patients were not seeking treatment, but had agreed to take part in this study, and all were diagnosed with opioid use disorder, either moderate or severe.

These subjects were given dose of either 24mg or 32mg one week apart, and had complete suppression of opioid withdrawal at both doses. The subjects were then challenged with varying doses of hydromorphone, and had sustained blockade of response to the hydromorphone. [2]

The six-month implant, brand name Probuphine, hasn’t been widely prescribed. As I predicted, the confusion over cost, insurance coverage, and implantation regulations have so complicated Probuphine’s use that mainstream medical providers aren’t considering its use. Also, it’s only indicated for patients on 8mg or less of sublingual buprenorphine, and patients have concerns about what will happen if it doesn’t work well. They ask if their insurance companies would pay for supplemental buprenorphine if the implant doesn’t work as well for them. I don’t know for sure, but I’m guessing they would not pay for supplemental medication.                                                                                                                                                                                                                                                                                                                                                                                                                 My biggest concern with Probuphine was that patients may be less inclined to come for counseling sessions if they have had a six-month implant that keeps them feeling normal. They have no monthly incentive to see their physicians. Many physicians require counseling as a condition for ongoing monthly prescription for sublingual buprenorphine.

I like the idea of injections for weekly or monthly buprenorphine. If it works as well or better than sublingual buprenorphine, it could be the solution to some difficult problems.

  • It would save time for my patients on buprenorphine at the opioid treatment program. One of the complaints we hear is of the regulations surrounding treatment in our setting. Unlike in the office-based setting, buprenorphine prescribing at the opioid treatment program demands we follow the sometimes onerous rules of both state and federal laws governing opioid treatment programs.
  • It would resolve our diversion dilemma.But injections can’t be diverted, so far as I’m aware.
  • Because buprenorphine has a high street value in my community, patients are sometimes tempted to spit out their medication to sell it, or even to inject it into themselves. We don’t want this, given the high rates of complications with intravenous use. We don’t want patients to sell medication because it hurts our reputation in the community. We don’t want to be known as suppliers of illicit buprenorphine.
  • It would be a godsend for patients who have to go to jail unexpectedly.
  • Most of the time, jails won’t bring incarcerated patients to the OTP for their daily dose of buprenorphine (or methadone), so they suffer opioid withdrawal and are at risk for relapse upon being released, with increased risk of overdose death. But if we can give them a monthly or even weekly shot, it will keep them feeling better, and serve as a blocker if they do leave jail and use illicit opioids like Opana or oxycodone or heroin.
  • Patients wouldn’t have to think about taking medication each day; with the injections they wouldn’t have to take a dose of anything each day, just show up for weekly or monthly injections given to them by a medical professional
  • Subcutaneous injections are much less complicated to administer than Probuphine, with rods that require a minor surgical procedure to implant, then explant six months later.The FDA plans to discuss this new preparation of buprenorphine at their advisory committee meeting November 1, 2017. Several days prior to this meeting, data to be discussed at this meeting should be available online for interested readers. [3]If this new option is approved by the FDA, it can give us yet another tool with which to treat patients, always a good thing.
  • 1. Albayaty et al., Advanced Therapeutics, 2017, Feb; 34 (2)

 

  • 2.Walsh et al., JAMA Psychiatry, 2017;74(9):894-902.

 

Maximum Daily Dose of Buprenorphine

Hser et al., 2014, Addiction

 

 

 

 

 

I’d like to thank my readers for their patience during my recent break from blogging. Now that I’m rested, it’s time to start barbequing some sacred cows.

First on my list: limiting the dose of sublingual buprenorphine to 16mg per day.

Recently I’ve heard from physicians who have been told 16mg of sublingual buprenorphine is the highest daily dose that should be prescribed, because studies show that opioid receptors in a human brain are saturated at that dose in most people. While this is true, limiting all patients to 16mg or less neglects research from real life patients.

Some governmental agencies have gone as far as forbidding daily doses higher than 16mg. For example, the Virginia Board of Medicine passed a regulation earlier this year that the highest dose that physicians could prescribe was 16mg per day. In Tennessee, patients can’t go above 16mg per day unless they are seen by an addiction specialist physician.

However, the FDA has approved doses up to 24mg SL per day. Who is right? Did the FDA get it wrong? Are patients who want to go higher than 16mg all drug seekers? Or do all such patients plan to sell their excess medication?

If you read the REMS document created by the manufacturer of Suboxone film, it says the target dose should be no higher than 16mg per day, and that doses higher than 24mg haven’t been shown to provide additional benefit. That leaves a question mark about dosing between 16 and 24mg.

The American Society of Addiction Medicine (ASAM) issued a statement addressing the tendency of state prescription monitoring programs to assign MME (morphine milligram equivalents) values to buprenorphine doses. In that statement, issued earlier in 2017, they said, “The US Food and Drug Administration (FDA) approves dosing to a limit of 24 mg per day. There is some evidence regarding the relative efficacy of higher doses.” [1]

If ASAM says 24mg is OK for some patients, and the FDA has already approved that dose, that’s good enough for me…assuming the patient truly needs a higher dose.

Some patients do better on a dose of 24mg than on 16mg. I work at an opioid treatment program where we observe the patients taking their doses on site, and we pay close attention to any attempt at diversion of the dose. Therefore, we have no question about whether a patient is taking less than the dose I’m prescribing.

When I see new patients within a week or two of admission, I ask how they are feeling. Some patients dosing at 16mg per day of buprenorphine describe symptoms consistent with opioid withdrawal by late evening. I increase their dose above 16mg when I also see physical signs of withdrawal, like large pupils, sweaty palms, and the like. Many patients feel improvement to the point we don’t have to consider switching to methadone.

I increase these patients’ doses because I am sure they are getting their full dose each day, and because I see signs of withdrawal with my own eyes. I know experts say a dose of 16mg is “supposed” to block all the opioid receptors according to studies of this drug, and I believe that is true for many patients. I also think there are patients for whom increasing the dose above 16mg provides benefit, and can eliminate the need to switch to methadone.

Not that there’s nothing wrong with methadone. It has a proven track record, but it does have more medication interactions than buprenorphine, and is more dangerous with certain medical problems.

Methadone patients were under-dosed for years, when physicians had the misperception that no patient needed more than 70mg per day to treat withdrawal. With further studies and information, we know that’s not true, and best evidence shows most patients need between 80-120mg, and sometimes much more than that.

I think in years to come, we will see that by limiting patient doses to 16mg, we are under-dosing some buprenorphine patients.

Why are so many agencies trying to keep buprenorphine doses low?

First, the U.S. has a “less is more” attitude regarding medication-assisted treatments for opioid use disorder. Given the existing bias against these medications, of course some peoples’ attitudes will be grudging acceptance of the medications, but trying to limit the doses to be as low as possible.

Second, there’s the very real concern about diversion of buprenorphine. The more buprenorphine that’s being prescribed and dispensed, the more that may end up being diverted to the black market. I know this is true.

However, opinions can differ regarding the potential harm of providing more buprenorphine to the black market. Some experts might think since buprenorphine is one of the safest opioids manufactured, increased black market access could help save lives. Though many more people embrace harm reduction now than ten years ago, we are not yet in a place where the law-and- order types would allow a serious conversation about this.

Third, I’m worried that some decisions about dose maximums for buprenorphine may be driven by cost. In a state where many patients prescribed buprenorphine products are on Medicaid, higher doses would cost the state more. The same would be true for managed care organizations and the insurance companies and the like. I hate to sound cynical, but financial concerns often drive medical decisions.

By now you know my opinion; if a patient dosing with buprenorphine 16mg SL per day reports withdrawal symptoms and has physical signs that match these symptoms, I’m willing to increase the dose to 20 to 24mg per day. We have a pretty good study, by Hser et al., 2014, that shows higher treatment retention rates with higher doses. Plus, the FDA has already approved doses up to 24mg per day. [2]

I’m cautious about take home dose in patients at the opioid treatment program. If the patient has a history of injecting drugs, I’d like them to have more time in stable recovery before granting take homes. For patients on 24mg per day, I may do more frequent pill counts and bottle recalls, as a precaution against drug diversion. But I’m not sure a patient on 16mg is any less likely to sell part of her prescription than a patient dosing at 24mg.

  1. https://www.asam.org/advocacy/find-a-policy-statement/view-policy-statement/public-policy-statements/2016/10/11/public-policy-statement-on-morphine-equivalent-units-morphine-milligram-equivalents
  2. Hser et al., “Treatment Retention among Patients Randomized to Buprenorphine/naloxone Compared to Methadone in a Multi-site Trial,” Addiction, 2014, Jan; 109(1) 78-87.