Micro dosing of Buprenorphine: Is it an Option Yet?

We all know fentanyl has taken over as the main opioid of use for patients with opioid use disorder. We have three medications that treat opioid use disorder, but some practitioners feel buprenorphine induction has become problematic for some fentanyl users. Even after waiting until patients are in moderate withdrawal, with a COWS (Clinical Opioid Withdrawal Score) of 12 or above, some of these patients have precipitated withdrawal symptoms after their first dose of buprenorphine, with either the mono- or combo product.

Why is this?

Since fentanyl has a relatively short duration of action, we might expect that if we wait until patients have at least moderate withdrawal, starting buprenorphine would be OK. But experts say that fentanyl is lipophilic, meaning it gets distributed into peripheral tissues in a non-dose-dependent fashion. For patients who have been using fentanyl long and hard, the drug has a large volume of distribution and may dissipate slowly, thus causing precipitated withdrawal after administration of the less potent buprenorphine, even if the patient feels a moderate or higher degree of withdrawal.

What can be done about this?

Some physicians ask patients using fentanyl to wait 24 to 48 hours after their last use of fentanyl to take that first dose of buprenorphine. This approach reduces the risk of precipitated withdrawal… but is extremely difficult for patients. No one likes to be sick, and enduring opioid withdrawal for nearly two days is too much for some patients.

At the opioid treatment program, I’ve had only a few cases of precipitated withdrawal in such patients. Patients I treat usually know how long they must wait to take buprenorphine, from prior experience using buprenorphine illicitly for their opioid withdrawal. I can use their knowledge. I do shared decision-making with the patient for the best outcome. Some patients, having had precipitated withdrawal from buprenorphine products in the past, want no part of this medication, and want to start methadone.

That’s fine with me. Methadone has been around for decades and works very well to treat opioid use disorder. It’s a more complicated medication, but is as good as buprenorphine, and studies show methadone retains patients in treatment longer. But office-based practitioners can’t prescribe methadone to treat opioid use disorder. That’s illegal.

Now there may be a new option for buprenorphine induction, called micro dosing. With this technique, patients don’t have to stop using opioids and wait for moderate withdrawal. Micro dosing eliminates the uncomfortable wait time and thus is more attractive to potential patients.

I’ve been scouring the internet for information about micro dosing protocols and have found several. An article from scientists in British Columbia from last year described their technique of micro-dosing buprenorphine. For this method, the patient can continue to use illicit opioids during the induction of buprenorphine, which is started in very low doses, compared to what we usually use. Then once the patient reaches 12mg of buprenorphine per day, the patient hopefully can stop using illicit opioids, without going into withdrawal. [1]

The article describes the following recipe:

  • Day 1: 0.5 mg once a day
  • Day 2: 0.5 mg twice a day
  • Day 3: 1 mg twice a day
  • Day 4: 2 mg twice a day
  • Day 5: 3 mg twice a day
  • Day 6: 4 mg twice a day
  • Day 7: 12 mg (stop other opioids)

Since new patients don’t have to stop using illicit opioids or experience withdrawal with this method, it may make treatment with buprenorphine products more attractive.

How do you dose patients at half a milligram since the lowest tablet and film on the market is a 2/.5mg dose? Even though drug manufacturers have not done studies to assure the active medication is evenly distributed over the film or throughout the tablet, patients have been cutting tablets and films for years. Right now, I have seven office-based patients doing a slow taper who are cutting their 2/.5mg film into multiple pieces, to take much lower doses as they ease off the last bit of medication.

I had one patient who said she could cut a 2mg film into sixteen pieces, with sharp scissors. Then she took one of the sixteenths every other day. I prescribed her one 2mg film per month for many months, until she forgot to take a dose, had no withdrawal, and stopped buprenorphine/naloxone altogether.

My point is that with sharp scissors, a 2/.5mg film can easily be cut into quarters, equaling a half milligram each, roughly.

The original method, called the “Bernese method,” called for starting at .2mg per day and gradually increasing to 12mg over nine days. There are case reports dating back to 2010 that give positive results for induction with this method.

Micro dosing has also been suggested for a quicker and less painful method to transition from methadone to buprenorphine. It’s difficult for some patients to tolerate methadone withdrawal symptoms for long enough to get started on buprenorphine in the traditional manner.

Patients who wish to switch from methadone to buprenorphine currently need to gradually lower their dose of methadone to 40mg or less, then miss several days of dosing before starting buprenorphine under our present protocols. It’s hard for patients to tolerate a slow taper, particularly if they are at doses above methadone 100mg. I usually recommend they lower by 5mg per week, so it takes many weeks to get the dose low enough to make the switch. Some patients get frustrated and chose to remain on methadone. Others get frustrated and drop out of treatment, incurring the risk of overdose death that we see in untreated opioid use disorder.

This micro dose method could help patients make the transition much more quickly and easily… if it works.

It’s an intriguing idea, giving us more options to treat patients. But after my internet search, I haven’t found any large studies of these micro dosing protocols, only a few case reports here and there. Before I try micro dosing, I’ll need more objective information and more expert opinion. Ideally, I’d like to read about results from many patients, transitioned from fentanyl or methadone in a controlled manner.

I also question the reason who people want patients to transition from methadone, which works well as a treatment for opioid use disorder. True, it doesn’t work for everyone, because no medication works for everyone. But it’s a good and acceptable treatment and if a patient is doing well, what is hoped to be achieved by the transition to buprenorphine? If it’s what the patient wants, that’s a great reason. Perhaps the biggest reason patients want to switch is the convenience of office-based treatment available with buprenorphine products. If the patient has side effects or medication interactions with methadone, those are great reasons to switch.

But in one case study, a woman was transitioned from methadone to buprenorphine because she was hospitalized and due to her medical illnesses, needed to live in a nursing home. No nursing home would accept her on methadone, but they would accept her on buprenorphine. That’s why she was switched. [2]

That is not a good reason. It’s an arbitrary reason that reveals the same old bias against methadone we’ve fought for years.

So yes, I agree with transitioning from methadone to buprenorphine if there’s reason to do so, but let’s not agree to do this if the decision is based on stigma.

In other news, at the other extreme, some emergency department practitioners are using high-dose buprenorphine induction to alleviate withdrawal symptoms more quickly. They feel a higher dose provides longer relief of withdrawal, until the patient can access dependable medication treatment for opioid use disorder. I will describe a new study that suggests this can be done safely and without much risk of precipitated withdrawal in my next blog post.

  1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6970598/
  2. Terasaki et al, “Transitioning Hospitalized Patients with Opioid Use Disorder from Methadone to Buprenorphine without a Period of Abstinence Using a Microdosing Protocol,” Pharmacotherapy, July 26, 2019.

18 responses to this post.

  1. Posted by Tom Reach on August 22, 2021 at 5:51 pm

    I love the protocols! We have been doing this for years since fentanyl came out but not with such a clear program. Thanks for the insight

    Reply

    • Did you keep data? It could be very helpful. I get the feeling providers have been doing this but not many are recording the outcomes in an official-type record that could be published.

      Reply

  2. Posted by William Taylor on August 22, 2021 at 6:47 pm

    Butrans patches (5 mcg per hr through 20 mcg per hr) are another way to introduce low dose buprenorphine to someone at risk for precipitated withdrawal.. The slow onset from transdermal absorption may be less likely to set off precipitated WD than the rapid onset of sublingual administration. Not usually carried in an OTP though.

    Reply

  3. Posted by Caramello on August 23, 2021 at 12:46 am

    We’ve been doing this for a while. We’re in Australia, so minimal (if any) fentanyl – but have used microdosing to move from methadone to buprenorphine. The long acting injections are very popular, and work brilliantly. Lots of people want to move over. Precipitated withdrawal is, in my experience, substantially reduced using microdosing. Commencing with transdermal patches concurrent with methadone seems to work well in a 9-14 day process, gradually moving over to Suboxone in a sort of cross titration process – but after the first few days we’re still feeling our way in, and there is a variety of responses by our patients. None wholly negative, several very positive. Unfortunately, it is not part of a research project and difficult to share.

    Reply

  4. Posted by Sparky on August 23, 2021 at 5:41 am

    Just goes to prove that naloxone does nothing in buprenorphine,it should be removed and available to all of us without naloxone,they don’t know how buprenorphine works when it all comes down to it,they really have no idea

    Reply

  5. Posted by william taylor, MD on August 23, 2021 at 3:25 pm

    Have used butrans a couple of times for pain patients where I wanted to add buprenorphine to the existing pain regimen. No precipitated WD. Bunavail would have worked for addiction patients but has been removed from the market after commercial failure. Even the DEA might have a tough time going after a provider for using butrans when the exact same drug is used legally as sublingual buprenorphine.

    Reply

  6. Posted by vivivianita on August 30, 2021 at 4:09 pm

    Hi are any of you in the Los Angeles area or do you know of anybody who follows this protocol? Ideally, I would also like a recommendation for a rehab facility which could provide this kind of detox and follow up treatment. Please let me know

    Reply

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