Mike, from a previous PsychSnap, was started on buprenorphine for his moderate opioid use disorder using the “traditional” approach that required him to be in opioid withdrawal from non-prescribed oxycodone prior to the first dose of buprenorphine. He was stable on buprenorphine 16mg for six months until he heard that a childhood friend died in a car accident. When Mike went back to his hometown for the funeral, he was introduced to fentanyl by a high school friend as a way to numb the pain of their friend’s death. Mike stopped the buprenorphine and found himself smoking fentanyl multiple times a day for 2 weeks, needing more and more to avoid feeling sick. His girlfriend found fentanyl in his bathroom and told Mike that it was the drugs or her. She couldn’t stand by while he risked death when his friend just died! Mike sets up a video visit and asks you, his PCP, for help. He doesn’t want to go to a methadone clinic and asks if he can just restart the buprenorphine today or if he needs to get sick first to restart in the same way he did for oxycodone, the “traditional” approach?
What is different about fentanyl and treating fentanyl use disorder?
Using the lightbulb analogy that was introduced in the previous buprenorphine PsychSnap, full opioid receptor agonists like fentanyl turn the light on all the way. Buprenorphine, as a partial agonist with high affinity for the opioid receptor, is a dimmer switch that turns the light on to 50%. To avoid precipitated withdrawal (sudden, uncomfortable dimmed light), the buprenorphine start for a patient using fentanyl needs to be done particularly carefully because fentanyl is not a “fast-on, fast-off” (the opioid receptor) substance. Fentanyl is highly lipophilic and settles into a fentanyl “depot” in adipose tissue when it is used chronically (Encinas 2013, Curbsiders Addiction Medicine Podcast Episode). The fentanyl from the adipose tissue (and other compartments of distribution) will slowly and continuously re-enter the circulation and bind with the opioid receptor in the brain for days even after a person has stopped using fentanyl.
As people using fentanyl are at a higher risk of precipitated withdrawal from buprenorphine than people using other short-acting opioids, a longer period of time of not using fentanyl is necessary (given fentanyl’s pharmacokinetic properties above) before starting buprenorphine (Shearer 2022, Varshneya 2021). Experts often recommend that patients wait at least 48-72 hours after last fentanyl use before starting buprenorphine rather than the 12 hours recommended for other short-acting opioids because of this risk of precipitated withdrawal.
Is there another way to start buprenorphine in the clinic for someone using fentanyl?
Overlapping, low-dose buprenorphine starts introduce the patient to low doses of buprenorphine that slowly increase over 3-10 days, while the patient might continue to use the full opioid agonist (De Aquino 2021). The patient takes the low dose of buprenorphine before the fentanyl to minimize the chance of precipitated withdrawal. When the buprenorphine is taken first, it will occupy some of the opioid receptors (as a partial agonist) and the fentanyl occupies what’s left. If taken in the reverse order and with higher doses of buprenorphine, the fentanyl that’s sitting on the receptors will be knocked off by the buprenorphine, causing precipitated withdrawal. In low dose starts, once a patient reaches a therapeutic dose of buprenorphine, the full opioid agonist (which, in this case is fentanyl) is discontinued. The final dose of buprenorphine should ideally address fentanyl cravings and opioid withdrawal symptoms, though realistically it may not completely cover them. By taking both the full opioid agonist and increasing doses of buprenorphine for several days, patients can reduce their likelihood of developing significant withdrawal or cravings, and maintain pain control, if that is relevant, while buprenorphine is started.
The data in terms of RCTs and high-quality studies comparing traditional (withdrawal-based) starts like the one Mike did in the first buprenorphine PsychSnap and low-dose, overlapping starts is limited. We have no RCTs that show that low-dose starts are better or that there isn’t any withdrawal during the process. We do have case reports that this overlapping, low-dose approach (especially in the ambulatory setting) helps patients start buprenorphine while avoiding a period of significant withdrawal during buprenorphine initiation (Karavolis 2022, Noel 2023). We think that low-dose, overlapping starts are an important tool in the PCP toolkit for caring for patients with fentanyl use disorder because patients avoid being in significant withdrawal for several days while waiting to start buprenorphine.
There are a number of different low-dose protocols for initiating buprenorphine. They vary in length (3-10 days) and the types of buprenorphine formulations used (patch, buccal film, sublingual film) (Cohen 2021, Sokolski 2023, Curbsiders Addiction Medicine Episode: Low Key Pearls for Low Dose Bup 2023). I am including two protocols for a slow overlapping buprenorphine start for someone using fentanyl. One offers clear instructions for patients and is adapted (with permission) from a team in the Bay Area, including Dr. Nicky Mehtani. The other is a medication table for clinicians, published as the “Howard Street Method” by the team at OBIC (Noel 2023).
I hope that this will allow you to start buprenorphine slowly and safely in a patient with fentanyl use disorder to minimize the chance of significant withdrawal. Remember that some patients are not successful in their efforts to start buprenorphine until the 2nd or 3rd time, so if a patient isn’t able to get on buprenorphine the first time they try, there is still utility in trying again. Normalize the challenge, welcome them back to care, and offer supportive medications (e.g. hydroxyzine, ondansetron, loperamide, etc.) for any level of opioid withdrawal experienced in the low dose start.
If you need more support, please connect with addiction medicine experts in your area for local resources on how to do this best, or contact the National Clinician Consultation Center’s Substance Use Warmline that is available 9am-8pm EST Monday through Friday for substance use related questions answered by an addiction specialist.
Returning to Mike:
You meet with Mike in a video visit to discuss starting buprenorphine slowly. Once you describe the lightbulb analogy and buprenorphine’s power to turn the lightbulb immediately to 50% when the fentanyl may have had it at 100%, Mike understands why going slowly is important. He still has a few 2mg buprenorphine films from his last buprenorphine start and plans to cut them in fourths to start slowly as you recommend. You make a plan to follow up in 3 days to see how the initiation is going.
How do you follow-up with patients with opioid use disorder after starting buprenorphine?
Early in the buprenorphine initiation process more frequent check-ins are better. After the day 3 appointment, it’s helpful to have weekly appointments in-person or via telemedicine, the latter of which eliminates many barriers to starting and continuing buprenorphine (Wang 2021). At these appointments, clinicians and patients can check-in, adjust dosages, manage side effects, and revisit and personalize treatment goals. Cravings or using non-prescribed opioids would be a reason to increase the buprenorphine dose in increments of 2 or 4mg, with a usual maximum of 24mg daily. In the age of fentanyl, there are some patients who may need higher doses and some patients are maintained on buprenorphine doses up to 32mg to address cravings and withdrawal.
Side effects from the medication, most commonly headaches or nausea, may improve with switching from a combo product (buprenorphine-naloxone) to a mono product (buprenorphine alone), changing from films to tablets, or reducing the dose. Remember that abstinence is not the only positive treatment goal or outcome. Safer use, less chaotic use, a reduction in use, or an increased ability to function in the world (in the way the patient wants to) are also important positive outcomes.
Look for a future PsychSnap addressing how to switch from the sublingual buprenorphine formulations to extended-release formulations (brand name Brixadi or Sublocade) for convenience and improved adherence.
Key Points
1) Patients with a fentanyl use disorder are at higher risk of precipitated withdrawal when starting buprenorphine, requiring either a longer waiting period for a traditional start or a low dose, overlapping start.
2) Buprenorphine can be started with low-doses that slowly increase over several days and overlap with ongoing use of full agonist opioids to minimize withdrawal in patients with fentanyl use disorder.
3) The National Clinician Consultation Center’s Substance Use Warmline is a free resource that allows clinicians to discuss substance use related questions with an addiction specialist.
Related PsychSnaps:
How do you start buprenorphine for a patient with opioid use disorder? Era Kryzhanovskaya, June, 2024.
Curbsiders Episodes:
Cohen SM, Morford K, Weimer MB, Sonoda K, Stahl N, Chan, CA. #24 Treating OUD in the Fentanyl Era: ASAM Treatment Week with Dr Melissa Weimer. The Curbsiders Addiction Medicine Podcast. October 17, 2023.
Cohen S, Soran C, Mullins K, Chan CA #7 Do the OBOT: Buprenorphine for OUD in the Clinic with Dr. Christine Soran. The Curbsiders Addiction Medicine Podcast. August 18, 2022.
Kryzhanovskaya E, Sokolski E, Goff A, Leyde S, Chan CA “#22 Low Key Pearls for Low Dose Bup with Dr. Sokoloski and Amelia Goff, FNP”. The Curbsiders Addiction Medicine Podcast. September 19, 2023.
References:
Cohen SM, Weimer MB, Levander XA, Peckham AM, Tetrault JM, Morford KL. Low Dose Initiation of Buprenorphine: A Narrative Review and Practical Approach. J Addict Med. 2022 Jul-Aug 01;16(4):399-406. doi: 10.1097/ADM.0000000000000945.
De Aquino JP, Parida S, Sofuoglu M. The Pharmacology of Buprenorphine Microinduction for Opioid Use Disorder. Clin Drug Investig. 2021 May;41(5):425-436. doi: 10.1007/s40261-021-01032-7. Epub 2021 Apr 5. PMID: 33818748; PMCID: PMC8020374.
Encinas E, Calvo R, Lukas JC, Vozmediano V, Rodriguez M, Suarez E. A predictive pharmacokinetic/pharmacodynamic model of fentanyl for analgesia/sedation in neonates based on a semi-physiologic approach. Paediatr Drugs. 2013 Jun;15(3):247-57. doi: 10.1007/s40272-013-0029-1. PMID: 23657896.
Karavolis ZA, Roy PJ. Adapting low-dose buprenorphine induction to meet patient needs: A pilot study. Drug and Alcohol Dependence Reports. Volume 5, 2022, 100104, ISSN 2772-7246, https://doi.org/10.1016/j.dadr.2022.100104.
Noel M, Abbs E, Suen L, Samuel L, Dobbins S, Geier M, Soran CS. The Howard Street Method: A Community Pharmacy-led Low Dose Overlap Buprenorphine Initiation Protocol for Individuals Using Fentanyl. J Addict Med. 2023 Jul-Aug 01;17(4):e255-e261. doi: 10.1097/ADM.0000000000001154.
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.
Sokolski E, Skogrand E, Goff A, Englander H. Rapid Low-dose Buprenorphine Initiation for Hospitalized Patients With Opioid Use Disorder. J Addict Med. 2023 Jul-Aug 01;17(4):e278-e280. doi: 10.1097/ADM.0000000000001133.
Varshneya NB, Thakrar AP, Hobelmann JG, Dunn KE, Huhn AS. Evidence of Buprenorphine-precipitated Withdrawal in Persons Who Use Fentanyl. J Addict Med. 2022 Jul-Aug 01;16(4):e265-e268. doi: 10.1097/ADM.0000000000000922. Epub 2021 Nov 23. PMID: 34816821; PMCID: PMC9124721.
Wang L, Weiss J, Ryan EB, Waldman J, Rubin S, Griffin JL. Telemedicine increases access to buprenorphine initiation during the COVID-19 pandemic. J Subst Abuse Treat. 2021 May;124:108272. doi: 10.1016/j.jsat.2020.108272
Send a Comment