This article was published on July 25, 2022. It was last edited/ updated on July 27, 2022.
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The initial treatment of persons who have been using fentanyl may involve not only addiction specialists but many of us non-specialists as well. We may these patients in emergency rooms, on inpatient mental health units, while doing consults on non-psychiatric units in the hospital, and so on.
So, all of us should be aware that there are serious problems that can occur in fentanyl users if standard treatments of opioid use disorder are used without being aware of the special issues in treating opioid use disorder when fentanyl or a fentanyl analog are involved. Let’s now discuss the main ones.
Buprenorphine initiation might precipitate withdrawal symptoms in fentanyl users
In North America, the use of illicit fentanyl is replacing the use of heroin (Thakrar, 2022). And, in many fentanyl users, initiation of treatment with buprenorphine can precipitate withdrawal symptoms (Thakrar, 2022).
Why would this be? Here are some reasons:
– Fentanyl has a long half-life—about 10 hours.
– Fentanyl is highly lipophilic, so, it goes into fat cells and gets stored there (Antoine et al., 2022). Due to this, when the person stops using fentanyl, it takes several days to leave the body, longer than we would expect (Huhn et al., 2020).
– Buprenorphine is a partial agonist at mu opioid receptors. So, if the effects of fentanyl are still present at opioid receptors, buprenorphine would act as an antagonist and precipitate opioid withdrawal.
This is not just a hypothesis. There are many published cases of buprenorphine precipitating opioid withdrawal in persons with fentanyl addiction (e.g., Antoine et al., 2022; Shearer et al., 2022; Quattlebaum et al., 2022; Thakrar, 2022).
We also have data from a large study that support this. In that study:
– In patients who were treated within 24 hours after the last use of fentanyl, being treated with buprenorphine was associated with 5 times greater odds of developing severe withdrawal symptoms compared to those who received methadone in the same situation (Varshneya et al., 2021). Of these persons, 22% developed severe opioid withdrawal if they were given buprenorphine versus 12% if they were given methadone (Varshneya et al., 2021).
– In patients who were treated within 24 to 48 hours after the last use of fentanyl, being treated with buprenorphine was associated with 3 times greater odds of developing severe withdrawal symptoms compared to being treated with methadone (Varshneya et al., 2021).
Consistent with all of the above, there has been a huge increase in the mention in internet discussions (subreddits) of opioid withdrawal being precipitated by buprenorphine (Spadaro et al., 2022).
We are in the midst of an opioid epidemic with fentanyl and analogs replacing heroin and mixed into it, and tens of thousands of people are dying from fentanyl overdoses.
At a time like this, to find that our leading treatment for getting people to stop using opioids—buprenorphine/ naloxone—often makes these persons worse is really bad news.
The title of a paper on this topic highlights the clinical problem:
“A Plea From People Who Use Drugs to Clinicians: New Ways to Initiate Buprenorphine are Urgently Needed in the Fentanyl Era” (Sue et al., 2022).
Option 1 for reducing the risk of buprenorphine precipitating opioid withdrawal
Option 1: Wait longer, reduce the first dose, but give doses more frequently and consider a higher final dose
1. For fentanyl addiction, consider waiting longer before starting buprenorphine
Given what we discussed above, what should we do? As of July 2022, the experts don’t agree. But, a potentially important recommendation has been made by some clinicians and is mentioned in the American Society of Addiction Medicine’s 2020 update to its guideline for the treatment of opioid use disorder.
These clinicians have suggested the following: In fentanyl opioid use disorder, we should wait until the person is in at least moderate opioid withdrawal (Clinical Opiate Withdrawal Scale score of 13 or more) before starting buprenorphine.
Waiting before starting buprenorphine is not the only change that is recommended in treating fentanyl addiction. Below, we’ll discuss other tips about this.
2. Reduce the first dose of buprenorphine
3. But, give doses more frequently
One group reported that in 2 patients with opioid use disorder that included the use of fentanyl, the initiation of 4 mg buprenorphine/ naloxone sublingual tablets 24 hours and 48 hours, respectively, after the last use of fentanyl precipitated moderate or severe opioid withdrawal (Antoine et al., 2022). So, they modified their approach for the next two patients as follows and opioid withdrawal was mild and manageable (Antoine et al., 2022). The 3 changes they made were:
– Waited until the COWS score was 13 or more before giving the first dose of buprenorphine/ naloxone
– Reduced the first dose of buprenorphine/ naloxone to 2 mg
– Gave subsequent doses of buprenorphine/ naloxone every 60 to 90 minutes, depending on the need.
Note: For simplicity, even though a combination of buprenorphine/ naloxone is used, only the dose of buprenorphine is mentioned in this article.
4. The final dose of buprenorphine may need to be higher than usual
This should not be surprising given that fentanyl is approximately 50 times more potent than heroin.
For the maintenance treatment of opioid dependence, the target daily dose of buprenorphine/naloxone sublingual film is typically 16 mg (Prescribing Information).
But, in one published case report, a patient with fentanyl opioid use disorder kept having withdrawal symptoms even after getting up to 32 mg/day of buprenorphine/ naloxone and eventually needed 40 mg/day of buprenorphine to be stabilized (Danilewitz and McLean, 2020).
Option 2: Low-dose initiation of buprenorphine (“microdosing”)
The urgent need for alternative ways of initiating buprenorphine in persons with fentanyl addiction has forced clinicians and fentanyl users to experiment with alternative approaches.
While there are no systematic studies of this approach (as of July 2022), one approach that is gaining in popularity is referred to as “low-dose initiation”, ‘‘microdosing’’, “microinduction”, or the “Bernese method”.
Optional to read: The American Society of Addiction Medicine’s update of its guideline for the treatment of opioid use disorder (American Society of Addiction Medicine, 2020) calls for research into ways of modifying buprenorphine initiation but does not discuss initiation by microdosing.
In this approach:
1. The full agonist opioid is continued throughout. This is a clear difference between this approach and what I called “Option 1” above.
2. Along with it, buprenorphine is started in very low doses (say, 0.5 mg/day) and slowly increased over many days.
The rationale for this approach is that with each increase in the buprenorphine dose, only small amounts of the full agonist opioid are displaced from the opioid receptor, which minimizes the risk of opioid withdrawal symptoms being precipitated by buprenorphine (Sue et al., 2022).
This “microdosing” approach to buprenorphine initiation has two advantages:
– It reduces the risk of precipitating opioid withdrawal.
– It reduces the severity of withdrawal symptoms overall. It is believed that large numbers of opioid users refuse to accept treatment due to a fear of having to go through significant opioid withdrawal symptoms (Suen et al., 2022).
It has been recommended that buprenorphine initiation by low dose overlap be considered as a first-line option for those who have a history of frequent fentanyl use or in whom buprenorphine had previously precipitated opioid withdrawal (Suen et al., 2022).
Option 3: Buprenorphine initiation by “ultrarapid microdosing”
Clinicians have also had success in accelerating buprenorphine initiation using a microdosing approach over only 2 to 3 days (for example, Azar et al., 2022).
For details of exactly how to do buprenorphine initiation using a microdosing or ultrarapid microdosing approach, please see the following article on this website:
Simple and Practical Medical Education thanks (alphabetically) Jonathan Beatty MD, and Marina Goldman, MD, for peer-reviewing and approving this article (in July and August 2022).
Dr. Beatty is a board-certified addiction psychiatrist in Philadelphia, Pennsylvania, who has extensive clinical experience in treating patients with substance use disorders. His clinical practice website is https://wavetreatmentcenters.com.
Dr. Goldman is a board-certified addiction psychiatrist. She is a Clinical Assistant Professor and Core Faculty in the Addiction Medicine & Addiction Psychiatry Fellowships at Thomas Jefferson University, Philadelphia, Pennsylvania. She also has a busy private practice in Jenkintown, Pennsylvania.
Opioid use disorder
Opioid use disorder—Management
Substance use disorders
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