This article was published on July 25, 2022. It was last edited/ updated on July 27, 2022.
Given the seriousness of the fentanyl epidemic and the huge number of people who are dying each year due to it, all articles on this website about fentanyl and fentanyl analogs are being made available to everyone and not only to our Members (subscribers). Please share these articles widely by email, social media, and other means.
Here are the links to the articles about fentanyl and fentanyl analogs:
Why we MUST know about fentanyl and fentanyl analogs
Special tests are needed to identify fentanyl in the urine
Special issues in using naloxone for overdoses involving fentanyl
Special points about managing fentanyl opioid use disorder
Special points in the management of fentanyl opioid use disorder (addiction)
Fentanyl analogs and why they are so important
Why and how to use fentanyl test strips
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:
How to initiate buprenorphine using a microdosing approach
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.
Related Pages
Fentanyl
Why we MUST know about fentanyl and fentanyl analogs
Special tests are needed to identify fentanyl in the urine
Special issues in using naloxone for overdoses involving fentanyl
An overview of fentanyl opioid use disorder (addiction)
Special points in the management of fentanyl opioid use disorder (addiction)
Fentanyl analogs and why they are so important
Why and how to use fentanyl test strips
Opioid use disorder
Opioid use disorder is a VERY serious condition
Opioids in the urine drug screen
Opioid use disorder—Management
Medication-assisted treatment (MAT) for opioid use disorder
Clinical pearls on prescribing buprenorphine (Suboxone®)
Clinical pearls about prescribing buprenorphine: Part Two
Buprenorphine (Subutex®, Suboxone®)
How to initiate buprenorphine using a microdosing approach
Buprenorphine extended-release injection (Sublocade®)
Naltrexone (Revia®, Vivitrol®): Basic information
Tips on using naltrexone extended-release injectable (Vivitrol®)
Naltrexone extended-release injection (Vivitrol®): The how to
News: July 7, 2016. Buprenorphine prescribing limit raised significantly
Tips for our opioid-dependent patients
Loperamide abuse: Tips for mental health clinicians
NeuroStim System-2 (NSS-2) BRIDGE
Substance use disorders
Practice guidelines for substance-related and addictive disorders
How to learn addiction psychiatry
SAMHSA National Helpline (Treatment Referral Routing Service)
Tips on dealing with “slips” in recovery
Never crave alone
References
Adams KK, Machnicz M, Sobieraj DM. Initiating buprenorphine to treat opioid use disorder without prerequisite withdrawal: a systematic review. Addict Sci Clin Pract. 2021 Jun 8;16(1):36. doi: 10.1186/s13722-021-00244-8. PMID: 34103087; PMCID: PMC8186092. Review of published cases of initiation by microdosing or bridging with a buprenorphine patch.
Ahmed S, Bhivandkar S, Lonergan BB, Suzuki J. Microinduction of Buprenorphine/Naloxone: A Review of the Literature. Am J Addict. 2021 Jul;30(4):305-315. doi: 10.1111/ajad.13135. Epub 2020 Dec 30. PMID: 33378137. Review of published cases.
American Society of Addiction Medicine. The ASAM National Practice Guideline for the Treatment of Opioid Use Disorder: 2020 Focused Update. J Addict Med. 2020 Mar/Apr;14(2S Suppl 1):1-91. doi: 10.1097/ADM.0000000000000633. Erratum in: J Addict Med. 2020 May/Jun;14(3):267. PMID: 32511106.
Antoine D, Huhn AS, Strain EC, Turner G, Jardot J, Hammond AS, Dunn KE. Method for Successfully Inducting Individuals Who Use Illicit Fentanyl Onto Buprenorphine/Naloxone. Am J Addict. 2021 Jan;30(1):83-87. doi: 10.1111/ajad.13069. Epub 2020 Jun 23. PMID: 32572978; PMCID: PMC7755703.
Azar P, Mathew N, Mahal D, Wong JSH, Westenberg JN, Schütz CG, Greenwald MK. Developing A Rapid Transfer from Opioid Full Agonist to Buprenorphine: “Ultrarapid Micro-Dosing” Proof of Concept. J Psychoactive Drugs. 2022 Feb 13:1-8. doi: 10.1080/02791072.2022.2039814. Epub ahead of print. PMID: 35152847.
Bhatraju EP, Klein JW, Hall AN, Chen DR, Iles-Shih M, Tsui JI, Merrill JO. Low Dose Buprenorphine Induction With Full Agonist Overlap in Hospitalized Patients With Opioid Use Disorder: A Retrospective Cohort Study. J Addict Med. 2021 Dec 23. doi: 10.1097/ADM.0000000000000947. Epub ahead of print. PMID: 34954743.
Brar R, Fairbairn N, Sutherland C, Nolan S. Use of a novel prescribing approach for the treatment of opioid use disorder: Buprenorphine/naloxone micro-dosing – a case series. Drug Alcohol Rev. 2020 Jul;39(5):588-594. doi: 10.1111/dar.13113. PMID: 32657496; PMCID: PMC7919736.
Button D, Hartley J, Robbins J, Levander XA, Smith NJ, Englander H. Low-dose Buprenorphine Initiation in Hospitalized Adults With Opioid Use Disorder: A Retrospective Cohort Analysis. J Addict Med. 2022 Mar-Apr 01;16(2):e105-e111. doi: 10.1097/ADM.0000000000000864. PMID: 34001775; PMCID: PMC8595358. This article was not referenced on this page because the role of fentanyl in these cases was not clear.
Danilewitz M, McLean M. High-dose buprenorphine for treatment of high potency opioid use disorder. Drug Alcohol Rev. 2020 Feb;39(2):135-137. doi: 10.1111/dar.13017. Epub 2019 Nov 25. PMID: 31769109.
Hailozian C, Luftig J, Liang A, Outhay M, Ullal M, Anderson ES, Kalmin M, Shoptaw S, Greenwald MK, Herring AA. Synergistic Effect of Ketamine and Buprenorphine Observed in the Treatment of Buprenorphine Precipitated Opioid Withdrawal in a Patient With Fentanyl Use. J Addict Med. 2021 Nov 16. doi: 10.1097/ADM.0000000000000929. Epub ahead of print. PMID: 34789683.
Hämmig R, Kemter A, Strasser J, von Bardeleben U, Gugger B, Walter M, Dürsteler KM, Vogel M. Use of microdoses for induction of buprenorphine treatment with overlapping full opioid agonist use: the Bernese method. Subst Abuse Rehabil. 2016 Jul 20;7:99-105. doi: 10.2147/SAR.S109919. PMID: 27499655; PMCID: PMC4959756.
Hartley J, Rieke E, Blazes C, Smith B, Gregg J. Successful Transition from Fentanyl to Buprenorphine in a Community-based Withdrawal Management Setting. J Addict Med. 2022 Jul 21. doi: 10.1097/ADM.0000000000001014. Epub ahead of print. PMID: 35861342.
Huhn AS, Hobelmann JG, Oyler GA, Strain EC. Protracted renal clearance of fentanyl in persons with opioid use disorder. Drug Alcohol Depend. 2020 Sep 1;214:108147. doi: 10.1016/j.drugalcdep.2020.108147. Epub 2020 Jul 2. PMID: 32650192; PMCID: PMC7594258.
Jegede O, Parida S, De Aquino JP. Buprenorphine Treatment of Fentanyl-Related Opioid Use Disorder. Prim Care Companion CNS Disord. 2022 Apr 26;24(3):21cr03163. doi: 10.4088/PCC.21cr03163. PMID: 35486939.
Mars SG, Rosenblum D, Ciccarone D. Fentanyl: the many challenges ahead. Addiction. 2019 May;114(5):785-786. doi: 10.1111/add.14587. Epub 2019 Mar 15. PMID: 30873700.
Marwah R, Coons C, Myers J, Dumont Z. Buprenorphine-naloxone microdosing: Tool for opioid agonist therapy induction. Can Fam Physician. 2020 Dec;66(12):891-894. French. doi: 10.46747/cfp.6612891. PMID: 33334955; PMCID: PMC7745932.
Morris NP. Opioid Use Disorder Treatment in the Age of Fentanyl. JAMA Intern Med. 2022 Mar 1;182(3):249-250. doi: 10.1001/jamainternmed.2021.8114. PMID: 35099514.
Quattlebaum THN, Kiyokawa M, Murata KA. A case of buprenorphine-precipitated withdrawal managed with high-dose buprenorphine. Fam Pract. 2022 Mar 24;39(2):292-294. doi: 10.1093/fampra/cmab073. PMID: 34173647.
Shearer D, Young S, Fairbairn N, Brar R. Challenges with buprenorphine inductions in the context of the fentanyl overdose crisis: A case series. Drug Alcohol Rev. 2022 Feb;41(2):444-448. doi: 10.1111/dar.13394. Epub 2021 Oct 13. PMID: 34647379; PMCID: PMC8926080.
Silverstein SM, Daniulaityte R, Martins SS, Miller SC, Carlson RG. “Everything is not right anymore”: Buprenorphine experiences in an era of illicit fentanyl. Int J Drug Policy. 2019 Dec;74:76-83. doi: 10.1016/j.drugpo.2019.09.003. Epub 2019 Sep 25. PMID: 31563098; PMCID: PMC6914257.
Spadaro A, Sarker A, Hogg-Bremer W, Love JS, O’Donnell N, Nelson LS, Perrone J. Reddit discussions about buprenorphine associated precipitated withdrawal in the era of fentanyl. Clin Toxicol (Phila). 2022 Jun;60(6):694-701. doi: 10.1080/15563650.2022.2032730. Epub 2022 Feb 4. PMID: 35119337.
Sue KL, Cohen S, Tilley J, Yocheved A. A Plea From People Who Use Drugs to Clinicians: New Ways to Initiate Buprenorphine are Urgently Needed in the Fentanyl Era. J Addict Med. 2022 Jan 11. doi: 10.1097/ADM.0000000000000952. Epub ahead of print. PMID: 35020693.
Thakrar AP. Short-Acting Opioids for Hospitalized Patients With Opioid Use Disorder. JAMA Intern Med. 2022 Mar 1;182(3):247-248. doi: 10.1001/jamainternmed.2021.8111. PMID: 35099508.
Thakrar AP, Kleinman RA. Opioid withdrawal management in the fentanyl era. Addiction. 2022 Apr 4. doi: 10.1111/add.15893. Epub ahead of print. PMID: 35373864.
Varshneya NB, Thakrar AP, Hobelmann JG, Dunn KE, Huhn AS. Evidence of Buprenorphine-precipitated Withdrawal in Persons Who Use Fentanyl. J Addict Med. 2021 Nov 23:10.1097/ADM.0000000000000922. doi: 10.1097/ADM.0000000000000922. Epub ahead of print. PMID: 34816821; PMCID: PMC9124721.
Volkow ND. The epidemic of fentanyl misuse and overdoses: challenges and strategies. World Psychiatry. 2021 Jun;20(2):195-196. doi: 10.1002/wps.20846. PMID: 34002497; PMCID: PMC8129846.
Copyright © 2022, Simple and Practical Medical Education, LLC. All rights reserved. May not be reproduced in any form without express written permission. Disclaimer: The content on this website is provided as general education for medical professionals. It is not intended or recommended for patients or other laypersons or as a substitute for medical advice, diagnosis, or treatment. Patients must always consult a qualified health care professional regarding their diagnosis and treatment. Healthcare professionals should always check this website for the most recently updated information.
Leave a Reply: