How do you start buprenorphine for a patient with opioid use disorder?

Mike is a 37 year old man with persistent depressive disorder (formerly dysthymia) who presents to establish primary care. His girlfriend is with him, and he’s okay speaking in front of her about his medical history. Mike starts off the visit saying he wants to discuss opioids. He had a few injuries playing basketball 15 years ago that had him going in and out of the ER. At one visit, he was prescribed oxycodone for his pain. He continued to take oxy because it lifted his mood. Mike says he craved that feeling, and when he asked around for more oxy, a friend sold him oxy 30s. He’s been taking 3-4 a day for the last decade. You ask more questions about function, what he likes and doesn’t like about the oxy (using non-judgmental wording), and assess for a substance use disorder, as reviewed in previous PsychSnaps.

You thank Mike for sharing this information with you today and reflect that the oxy has made his life more difficult recently. He noted he’s been nodding off at work and sweating and agitated when he couldn’t get an oxy, which disrupts time with his girlfriend. You share the diagnosis of moderate opioid use disorder with Mike based on his cravings, withdrawal, time spent getting the oxycodone, relationship troubles, and role failure at work. Mike tells you that he heard about fentanyl getting into the drug supply (including street pressed pills) and doesn’t want to die. This worry, along with the trouble the oxy’s got him in at work and at home led Mike to realize he needed to find a way off the oxy. A friend recently offered him “subs” when he was in withdrawal, which helped him.

How do you start buprenorphine for a patient with an opioid use disorder (OUD)?

As background, there are 3 FDA-approved medications for the treatment of OUD:

  • Methadone: only available through an opiate treatment program (“methadone clinic”) for people with OUD, effective with significant mortality reduction (Wakeman 2020)
  • Extended-Release Naltrexone IM: only acceptable for a minority of people with limited data on treatment retention and overdose prevention (Jarvis 2018, Larochelle 2018)
  • Buprenorphine: can reduce mortality by 50% (like methadone) and can be started today (Sordo 2017, Larochelle 2018)
    • You do NOT need a waiver to prescribe buprenorphine for OUD. As of January 2023, neither an x-waiver nor a notice of intent (NOI) is required to prescribe buprenorphine for OUD in the United States. Anyone with a DEA license who can prescribe opioids can prescribe this life-saving medicine.  

You share with Mike that the “subs” his friend gave him is Suboxone,™ the brand name for the buprenorphine combo product (buprenorphine-naloxone), which is one of the FDA-approved OUD treatments. It can be taken under the tongue in either tab or film form to help address the cravings, withdrawal, and other symptoms of OUD. Mike is excited to start but he says another friend told him something that freaked him out: subs can also make you feel sick! What is Mike’s friend referring to? The syndrome of precipitated withdrawal. Let’s take a quick dive into pharmacology to explain this. 

How does buprenorphine work?
Buprenorphine is a high-affinity partial agonist at the mu-opioid receptor with a respiratory ceiling effect. 

  • High-affinity means that buprenorphine binds the mu-opioid receptor tighter than other opioids. People whose receptors are already saturated with buprenorphine are also protected from an overdose if additional opioids are taken. 
  • Partial agonism means that the mu-opioid receptor is partially (~halfway) activated, which is enough to reduce (and hopefully eliminate) cravings and withdrawal (Coe 2019). The analogy of a lightbulb may be helpful in talking to patients about partial agonism. Full mu-opioid receptor agonists like methadone, heroin, fentanyl, and oxycodone turn the light on all the way. Buprenorphine is like a dimmer switch that turns the light to ~50% of its potential brightness (Curbsiders Addiction Medicine episode).
  • The ceiling effect means that there’s a “cap” on respiratory depression—higher doses of buprenorphine do NOT cause more respiratory depression. When buprenorphine is used alone (i.e. not combined with other CNS depressants), the risk of overdose is very low. 

Buprenorphine’s partial agonism and high binding affinity for the receptor also place patients at risk of precipitated opioid withdrawal when they first start the medication. If Mike takes buprenorphine too close in time to his last oxy pill while his mu opioid receptors are saturated with a full opioid agonist like oxycodone, the high-affinity buprenorphine will knock the oxycodone off the opioid receptor and bind there itself, causing a sudden shift from full agonism to partial agonism. The brightly lit room is now dimly lit, and the patient experiences severe, acute opioid withdrawal symptoms, known as precipitated withdrawal. This is why starting buprenorphine intentionally, often slowly, and cautiously is essential. 

How do we start buprenorphine for a patient who is predominantly using a non-fentanyl opioid?

The standard, most evidence-based approach to starting buprenorphine (referred to colloquially as a “traditional” start) for a patient with OUD necessitates a period of opioid withdrawal. Per the lightbulb analogy, as the patient is in withdrawal, the room is getting very dark such that when buprenorphine is taken, it will treat opioid withdrawal (and make the room brighter), rather than precipitate opioid withdrawal. I will cover the standard approach to starting buprenorphine here and save information on low dose, slow, overlapping buprenorphine starts for a future PsychSnap. Also, given fentanyl’s tricky pharmacodynamics and pharmacokinetics, we will dive into how to start buprenorphine for people who are predominantly using fentanyl in the future.

How do you start buprenorphine for a patient with an opioid use disorder?

  • Prescription: Sublingual buprenorphine tablets or films. The films take a shorter time to dissolve but taste worse. The tablets take a longer time to dissolve, but don’t taste as bad. Patients can boost saliva production to help the tablets or films dissolve by having a lozenge or eating spicy food or something citrus-y before taking the medication. The formulation is based on patient choice and what is accessible based on their insurance or pharmacy. 
  • Mono or combo product: Sublingual buprenorphine formulations are either mono (buprenorphine) or combo (buprenorphine and naloxone) products. The combo product of buprenorphine and the opioid antagonist naloxone exists as a deterrent to injecting buprenorphine. If the combo is taken sublingually, as prescribed, the naloxone is not absorbed. However, if the combo is injected, the naloxone is active and can trigger opioid withdrawal due to its opioid antagonism. Most patients start with the combo product, in part due to insurance coverage; if a patient is pregnant or has cirrhosis, the mono product may be a better choice. 
  • Labs: You do not need any labs before writing the buprenorphine prescription. A comprehensive urine drug screen can be helpful in clarifying what the patient may have been exposed to. For example, urine toxicology could clarify whether Mike has been recently exposed to fentanyl, or whether he is also using cocaine, but neither should delay the start of buprenorphine. A pregnancy test is also not necessary, as buprenorphine is safe (and recommended) in pregnancy.

How do you counsel patients to start taking buprenorphine?

  • Location (as low barrier as possible!): The current expert opinion is that patients like Mike should be encouraged to start buprenorphine at home or wherever they are most likely to feel most comfortable, not in a clinic. If possible, recommend that people take at least 3 days off work or other responsibilities to start buprenorphine and that they share some of their plan with supportive friends or family. Mike shares with his girlfriend that he is starting buprenorphine and tells his mom he’s starting to take a medicine that may make him feel unwell for a few days.  
  • When to start: To avoid precipitated withdrawal, you tell Mike to wait to start buprenorphine until he is in at least moderate opioid withdrawal. For short acting opioids like oxycodone, this means waiting a minimum of 12 hours from the last dose AND experiencing at least three opioid withdrawal symptoms. When asked about symptoms of opioid withdrawal (e.g. skin crawling, muscle aches, nausea, runny nose or eyes, goosebumps, anxiety or irritability, yawning), Mike notes his skin crawling, sweating, and feeling agitated when he’s “sick” or in withdrawal. Once Mike has waited the appropriate time (varies for patients, ~12-24hrs) AND is experiencing significant withdrawal (at least 3 symptoms), he can start taking the buprenorphine under the tongue to treat the withdrawal. 
  • Initial prescription: Send an initial prescription for twenty 8-2mg buprenorphine-naloxone (suboxone) films to cover the first week. Mike can cut these into halves (for the 4mg starting dose) or fourths to get to the 2mg start dose. The films are easier to cut than tablets. People taking daily doses of at least buprenorphine 16mg stay in treatment longer and have better outcomes than those taking lower doses (Raleigh 2017, Chambers 2023). 
  • Goals: Buprenorphine initiation Day 1 goal is to get out of withdrawal and Day 2 (and beyond) goal is to address cravingsWe give patients enough buprenorphine so that they can take 24mg for the initiation. Counsel patients that they may not need to use all of that! 
  • Day 1: Depending on how much oxy he was taking up to this point (and considering that a very small part may have had fentanyl in it), Mike can start with anywhere from 2mg to 4mg of buprenorphine. He would then repeat this dose every 2 hours until his withdrawal symptoms resolve–for many people this results in a total daily dose of 12-24mg. We would expect the buprenorphine to start to improve his symptoms within the first hour, with more withdrawal-relieving effect by 4 hrs after taking it sublingually.
  • Day 2: Mike should take his total day 1 dosage at the start of day 2. Specifically, if he took 2mg sections of the film four times throughout the day, then on day 2, he would take one full 8mg film in the morning. He would continue to monitor opioid withdrawal symptoms every 2 hours and take another 2mg dose if he notices withdrawal symptoms or cravings appearing later in the day.
  • Day 3: Mike would take his total day 2 dosage at the start of day 3. Let’s say Mike needed two more 2mg film sections on day 2, in addition to the 8mg that he took at the start of Day 2. He would then start day 3 with buprenorphine 12mg total (1.5 films). He may feel his withdrawal and cravings for oxycodone resolve at this daily dose or he may have severe cravings later in the day. The goal is to titrate the buprenorphine to eliminate opioid withdrawal, reduce cravings, and allow Mike to move forward with his life goals. 
  • Opioid Kick Pack: The hardest part of the traditional, withdrawal-based buprenorphine initiation is the first 12+hours when the patient is asked to endure opioid withdrawal. This withdrawal is not only uncomfortable; it is also a potential motivator to return to use even when patients like Mike are very motivated to stop. You can be empowered as a clinician to support patients during this period of withdrawal by prescribing medications or reviewing over the counter options to help symptoms. This symptom pack or “kick pack” includes medications like ondansetron 4mg q6h for nausea (#10), loperamide 2mg q8h for diarrhea (#5), acetaminophen or ibuprofen for muscle aches or joint pain, and clonidine (0.1mg tablet q6h, #4, with hold parameters on BP/dizziness) or hydroxyzine 25mg q8h (#5) for anxiety.
  • Follow up: I recommend an initial follow up visit (in-person, over video, or by telephone) on day 3 of the buprenorphine initiation, and weekly after that to address dose adjustments (based on cravings or use of other substances). 
  • Harm reduction: Given the realities of the deadly and unpredictable drug supply along with Mike’s concern about fentanyl in oxys, you make sure that he has naloxone spray available and that he knows where he can get fentanyl test strips to check his supply.

Key Points:

1) Buprenorphine reduces mortality for people with OUD by 50%. As a life saving medication, it should be offered to all patients with OUD.
2) All clinicians have an opportunity to save lives by prescribing buprenorphine for OUD.  Once a patient has been diagnosed with OUD, buprenorphine can be started at home, without  any prior labs or work-up.
3) Traditional withdrawal-based buprenorphine initiation includes waiting 12+ hours for moderate opioid withdrawal (at least 3 symptoms) and then starting buprenorphine 2-4mg.

Relevant previous PsychSnaps:

“How do you talk with patients about their substance use?”  Era Kryzhanovskaya, September 25, 2023

“Chaos with cannabis: How to diagnose and treat cannabis use disorder.” Era Kryzhanovskaya, June 30, 2023

”Coke and subs: Is suboxone maintenance for opioid use disorder contraindicated in someone with cocaine on urine screen?” Era Kryzhanovskaya, March 24, 2023

References:

DEA Drug Fact Sheet: https://www.dea.gov/sites/default/files/2021-05/Counterfeit%20Pills%20fact%20SHEET-5-13-21-FINAL.pdf

Curbsiders Episode: https://thecurbsiders.com/addiction-medicine-podcast/7-do-the-obot-buprenorphine-for-oud-in-the-clinic

ACOG guideline for OUD in pregnancy: https://www.acog.org/clinical/clinical-guidance/committee-opinion/articles/2017/08/opioid-use-and-opioid-use-disorder-in-pregnancy 

Chambers LC, Hallowell BD, Zullo AR, et al. Buprenorphine Dose and Time to Discontinuation Among Patients With Opioid Use Disorder in the Era of Fentanyl. JAMA Netw Open. 2023;6(9):e2334540. doi:10.1001/jamanetworkopen.2023.34540

Coe MA, Lofwall MR, Walsh SL. Buprenorphine Pharmacology Review: Update on Transmucosal and Long-acting Formulations. J Addict Med. 2019 Mar/Apr;13(2):93-103. doi: 10.1097/ADM.0000000000000457. PMID: 30531584; PMCID: PMC7442141.

Jarvis BP, Holtyn AF, Subramaniam S, Tompkins DA, Oga EA, Bigelow GE, Silverman K. Extended-release injectable naltrexone for opioid use disorder: a systematic review. Addiction. 2018 Jul;113(7):1188-1209. doi: 10.1111/add.14180. Epub 2018 Mar 24. PMID: 29396985; PMCID: PMC5993595.

Larochelle MR, Bernson D, Land T, Stopka TJ, Wang N, Xuan Z, Bagley SM, Liebschutz JM, Walley AY. Medication for Opioid Use Disorder After Nonfatal Opioid Overdose and Association With Mortality: A Cohort Study. Ann Intern Med. 2018 Aug 7;169(3):137-145. doi: 10.7326/M17-3107. Epub 2018 Jun 19. PMID: 29913516; PMCID: PMC6387681.

Raleigh MF. Buprenorphine Maintenance vs. Placebo for Opioid Dependence. Am Fam Physician. 2017 Mar 1;95(5):Online. PMID: 28290640.

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.

Sordo L, Barrio G, Bravo MJ, Indave BI, Degenhardt L, Wiessing L, Ferri M, Pastor-Barriuso R. Mortality risk during and after opioid substitution treatment: systematic review and meta-analysis of cohort studies. BMJ. 2017 Apr 26;357:j1550. doi: 10.1136/bmj.j1550. PMID: 28446428; PMCID: PMC5421454.

Wakeman SE, Larochelle MR, Ameli O, Chaisson CE, McPheeters JT, Crown WH, Azocar F, Sanghavi DM. Comparative Effectiveness of Different Treatment Pathways for Opioid Use Disorder. JAMA Netw Open. 2020 Feb 5;3(2):e1920622. doi: 10.1001/jamanetworkopen.2019.20622. Erratum in: doi: 10.1001/jamanetworkopen.2024.19798. PMID: 32022884; PMCID: PMC11143463.

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. Epub 2021 Jan 15. PMID: 33771276; PMCID: PMC7833481.

Wyse JJ, Morasco BJ, Dougherty J, Edwards B, Kansagara D, Gordon AJ, Korthuis PT, Tuepker A, Lindner S, Mackey K, Williams B, Herreid-O’Neill A, Paynter R, Lovejoy TI. Adjunct interventions to standard medical management of buprenorphine in outpatient settings: A systematic review of the evidence. Drug Alcohol Depend. 2021 Nov 1;228:108923. doi: 10.1016/j.drugalcdep.2021.108923. Epub 2021 Jul 29. PMID: 34508958; PMCID: PMC9063385.