Keep saving lives by prescribing methadone and buprenorphine. Learn how initiations of each have changed in the era of high-potency synthetic opioids (HPSOs) like fentanyl and how to continue to provide person-centered care to people with opioid use disorder. We’re joined by Dr Melissa Weimer, @DrMelissaWeimer (Yale University). This episode is in honor of National Addiction Treatment Week (treataddictionsavelives.org).
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The fourth wave of the U.S. overdose crisis stems from a rapid shift to high-potency synthetic opioids (HPSO), such as fentanyl and fentanyl analogs in the drug supply, contributing to over 100,000 deaths in the last year (CDC).
While the shift in opioid supply is often referred to as a shift to nonpharmaceutical fentanyl, in truth, other fentanyl analogs and synthetic opioids are present as well (Armenian 2018). The shift increased opioid supply potency, driving the surge in overdose deaths. Additionally, while nonpharmaceutical fentanyl is short-acting, its lipophilicity may lead to a longer terminal half-life resulting in prolonged withdrawal (Bird 2023, Comer 2019). These properties impact initiating opioid use disorder medications, necessitating more tolerable and person-centered approaches (Sue 2022, Buresh 2022, Weimer 2023).
MOUD remains an effective lifesaving treatment
It’s critical to note that despite these drug supply changes, MOUD, specifically methadone and buprenorphine, remain incredibly effective medications and one of our best tools for reducing the risk of overdose and mortality. Methadone and buprenorphine have been shown to reduce mortality by as much as 50% in studies including data in the era of fentanyl/HPSOs (Pearce, 2020, Wakeman 2020)!!!
For a thorough discussion about methadone, the regulations, and troubleshooting methadone in the inpatient and outpatient settings, check out the inaugural Curbsiders Addiction Medicine episode #1 Methadone for OUD w/ Dr Ruth Potee.
To start, Dr. Weimer highlights that there is a common misconception that due to regulations around methadone, it cannot be initiated in the hospital. This is FALSE; it is legal and the standard of care to initiate methadone in the hospital for someone with OUD (Code of Federal Regulations Title 21 Part 1306.07, Noska 2015, Martin 2023).
Before getting into the adaptations for methadone initiation in the era of HPSOs, it’s worth briefly reviewing how methadone is generally initiated and why. Methadone is a long-acting full opioid agonist with robust data for treating OUD. Due to its long half-life and variable pharmacokinetics, it generally takes 3-5 days to reach a steady state, and thus, the standard uptitration process is slow and gradual. In general, initiations of methadone begin with a dose of 20-30 mg on day 1 with uptitration by 5-10mg every 3-5 days (SAMHSA TIP 63, 2021, Chou 2014). There are also federal regulations for Opioid Treatment Programs that limit the first-day dose of methadone to no more than 40mg but these federal regulations do not apply to the hospital setting (Code of Federal Regulations Title 21 Part 1306.07).
In the era of HPSOs, there has been increasing awareness of the need to adapt initiations to individuals’ increased opioid tolerance and more severe opioid withdrawal from HPSOs (Buresh 2022). Methadone initiation has always been a balance of waiting for a steady state before titrating to reduce the risk of prolonged oversedation while getting to an effective dose quickly (individualized but generally >60mg per day). This is particularly critical as the first weeks of methadone initiation are a particularly high-risk time with increased mortality as people often continue to use opioids while on a subtherapeutic dose of methadone (Sordo 2017, Degenhardt 2009).
Fortunately, two recent studies have described more rapid approaches to methadone initiation in the hospital setting. While each had slightly different regimens the results were similar. Initiations began at 30-40mg and titrated by 10mg per day up to 60mg with very few adverse effects, including sedation (Klaire 2023, Racha 2023). One study even showed a reduction in premature discharges (Racha 2023).
In Dr. Weimer’s expert opinion and personal practice, she follows a similar up-titration regimen in patients with known regular HPSO use, severe opioid withdrawal, and stable medical conditions without significant respiratory compromise. She recommends that you should not follow this guidance unless you have experience using methadone. Additionally, individuals should be monitored 4 hours after their dose of methadone when the dose peaks, and if the person is sedated, that indicates that you need to revise and slow down the process. She also advises getting a baseline ECG before rapidly up-titrating methadone. For further discussions on QTc and methadone please see Curbsiders Addiction Medicine episode #1 Methadone for OUD w/ Dr Ruth Potee.
Dr. Weimer’s Example of rapid methadone initiation in the hospital setting
Day 1- 30mg first dose + 10mg PRN x2 (at least 4 hours apart) up to max total day 1 dose of 50mg
Day 2- Day 1 total dose in AM+ 10mg PRN x2 (at least 4 hours apart) up to max total day 2 dose of 60mg
Day 3- Day 2 total dose in AM, If at 60mg, hold there for 3-5 days, if not can uptitrate similarly to prior days
While more rapid initiations of methadone are helpful in controlling withdrawal symptoms, it is not a one-size-fits-all approach, and for some, withdrawal symptoms will remain. While opioid withdrawal is often framed as non-severe or non-life-threatening, it is a common reason why patients hesitate to seek hospital care and it can contribute to premature discharge due to untreated withdrawal symptoms, which is associated with higher mortality rates (McNeil 2014, Alrawashdeh 2023). We must reframe how we think about adequately treating opioid withdrawal as a standard of care to allow people to get the care they need in the hospital (Hughes 2023).
Dr. Weimer emphasized the need to use higher doses of short-acting opioids to treat opioid withdrawal and pain in someone with opioid use disorder given an increased opioid tolerance. For a longer discussion on treating acute pain in hospitalized patients with OUD check out Curbsiders #366 Opioid Use Disorder and Acute Pain in a Hospitalized Patient. It’s always important to consider the risks of respiratory depression and use high doses of opioids with caution in individuals with respiratory compromise (e.g. severe COPD, OSA, pneumonia, advanced age, etc).
For a thorough discussion about buprenorphine pharmacology, initiation, and troubleshooting, check out the Curbsiders Addiction Medicine episode #7 Do the OBOT: Buprenorphine for OUD in the Clinic with Dr Christine Soran. Since that episode, the X-Waiver has been removed, meaning that ANY clinician with a DEA license can now prescribe buprenorphine.
Before getting into the adaptations for buprenorphine initiation in the era of HPSOs, it’s worth briefly reviewing how buprenorphine is generally initiated and why. Buprenorphine is a partial opioid agonist with high affinity at the opioid receptor with robust data for the treatment of OUD (SAMHSA TIP 63, 2021). Practically, this means buprenorphine activates the opioid receptor enough to relieve cravings and withdrawal and has less of a risk of respiratory depression. Its high affinity at the opioid receptor means it grabs the receptor more tightly than other opioids, preventing other opioids from getting on the receptor (which protects from overdose) and also displacing other opioids currently on the opioid receptor (Volpe 2011).
Together the partial agonism and high affinity have a downside when combined – buprenorphine-precipitated opioid withdrawal (BPOW). If a standard dose of buprenorphine is given while someone has a full opioid agonist in their system, the buprenorphine replaces it. This causes a sudden drop from full agonism to partial agonism and SEVERE abrupt opioid withdrawal.
While BPOW is not yet well defined in the literature it can be thought of as a rapid increase in Clinical Opioid Withdrawal Scale (COWS) >5-10 points along with objective signs of opioid withdrawal (e.g. diarrhea, vomiting, dilated pupils, severe restlessness) after being given buprenorphine.
To minimize the risk of BPOW, traditionally, buprenorphine is initiated first by waiting for signs of opioid withdrawal (e.g. COWS >8) to indicate there isn’t a significant full agonist on the receptor and then giving buprenorphine 2-4 mg, which is repeated until symptoms improve (SAMHSA TIP 63, 2021).
For example traditional initiation regimen
Step 1: Stop all opioids/HPSOs
Step 2: If short-acting opioids (e.g., heroin, oxycodone), wait 12 hours and until signs of opioid withdrawal (e.g. COWS >8)
Step 3: Give buprenorphine 2-4mg
Step 4: Repeat buprenorphine every 2 hours until improvement of withdrawal symptoms
There is growing concern that HPSOs have made buprenorphine initiations more difficult. Due to its lipophilicity in particular, fentanyl and fentanyl analogs may take longer to clear from the body, which may increase the risk of significant or precipitated withdrawal (Silverstein 2019, Varshneya 2021, Sue 2022). It’s worth noting that some recent studies in the emergency department have shown rates of BPOW ranging from <1% of people exposed to HPSOs in a randomized trial to up to 5% of those exposed to HPSOs in a recent cohort study. (D’Onofrio 2023, Snyder 2023).
In Dr. Weimer’s expert opinion, there is likely both a slight increase in BPOW incidence as well as a component of untreated, ongoing opioid withdrawal when traditional lower doses (2-4mg of buprenorphine at a time) are used to initiate buprenorphine. She believes some of the increase in BPOW may be due to 1) the short-acting nature of HPSOs leading to some earlier withdrawal symptoms (e.g., anxiety, restlessness) and 2) the initiation of buprenorphine before it is deemed appropriate. In her practice, she has adapted by using different methods of buprenorphine initiation depending on the individual, the clinical situation, and the clinical setting (Weimer 2023).
High-dose buprenorphine initiation, or start, is a variation of traditional initiation in which higher doses of buprenorphine are used with each dose. This adaptation can be considered as a means to align buprenorphine initiations with the heightened opioid tolerance that develops through regular HPSO use. The process still involves stopping all opioids and waiting for significant symptoms of opioid withdrawal (COWS >8 with objective signs of opioid withdrawal) prior to starting buprenorphine (Herring 2021, Snyder 2023).
In Dr. Weimer’s practice and expert opinion, she typically recommends patients wait at least 48 hours following the last HPSO use and for at least one objective sign of opioid withdrawal (e,g,, mydriasis or piloerection) before starting buprenorphine. At that point, 8-16mg of buprenorphine is given and repeated every 2 hours to a maximum of 24-32 mg of buprenorphine on the first day. For a similar approach and great resource, please check out the CA BRIDGE ED quick start guide.
In cases in which the person is hospitalized and will be for a few days, Dr. Weimer often uses short-acting opioids and adjuvant treatments like clonidine and hydroxyzine for 1-2 days as a bridge/washout period for the HPSOs and then waits 8-12 hours from last short-acting opioid use and for withdrawal symptoms (including one objective sign) prior to doing a high dose initiation of generally 16-24mg as the first starting dose. This shortens the period of required abstinence from 48+ hours to 8-12 hours. However, it is important to note that legally, this approach is only permissible in the hospital setting due to restrictions on opioid use for the treatment of OUD in the outpatient setting.
Example high dose initiation regimen
Step 1: Stop all opioids
Step 2: Wait at least 48 hours from last HPSO use and until signs of opioid withdrawal (at least 1 objective sign) while giving adjuvant treatments decrease withdrawal symptoms
Step 3: Give buprenorphine 8-16mg
Step 4: Repeat buprenorphine every 2 hours until improvement of withdrawal symptoms (max dose 24-32 mg day 1)
For a more thorough discussion of low dose initiation) check out our recent episode #22 Low Key Pearls for Low Dose Bupe .
In brief, low-dose buprenorphine initiation is a completely different approach in which buprenorphine is started at small doses (generally <0.5mg) and gradually increased over days while a full opioid agonist is continued with the goal of avoiding significant opioid withdrawal entirely(Cohen, 2021). The small doses of buprenorphine and gradual increase in the buprenorphine dose displace only a small amount of full agonist from the receptor and thus reduces the risk of withdrawal. While indications and regimens vary institutionally, it is often considered most appropriate for people with OUD in acute pain requiring opioids (ie postoperative), people transitioning from methadone, and people who have had trouble with other methods of buprenorphine initiation.
Continuing a stable dose of full opioid agonists is critical to avoid withdrawal symptoms in this method. In the hospital setting, this can be achieved by using any opioid or a combination of opioids (such as oxycodone, hydromorphone, methadone). In the outpatient setting where prescriptions of opioids for the treatment of OUD is limited by law, the use of a full agonist is often limited to methadone through an opioid treatment program or continued use of the patient’s current supply of nonpharmaceutical opioids with harm reduction counseling about using as safely as possible (Weimer 2023).
In Dr. Weimer’s and Dr. Morford’s expert opinion, the process is much more difficult in the outpatient setting due to often complicated dosing strategies and difficulties with the full agonist. It is worth noting that there is supportive evidence for this practice, particularly with the use of blister packs to simplify the process (Noel 2023).
While the FDA approval for buprenorphine lists a maximum dose of 24 mg of buprenorphine per day, there is significant evidence that doses up to 32 mg may enhance the benefits of treatment (Grande 2023). In Dr. Weimer’s practice, if a patient continues to experience cravings, withdrawal, or exceeds their usage goals, she opts to uptitrate to 32 mg and also considers the potential transition to long-acting injectable (LAI) buprenorphine.
For more about LAI buprenorphine, check out episode #20 Extending Knowledge of LAI Buprenorphine with Dr. Ken Lee. In brief, LAI buprenorphine, particularly when continuing a higher dose such as Sublocade ® 300mg or Brixadi ® 128mg monthly, achieves higher and more consistent plasma concentrations of buprenorphine than sublingual buprenorphine even at 32mg (Haight 2019, Jones 2021). It can also take as long as 3-6 months to reach a steady state and thus additional sublingual buprenorphine may be needed, particularly during the first 1-3 months (Jones 2021).
Unfortunately, BPOW does happen and there is no robust data on how to treat it. It’s generally agreed that the first step is to optimize the use of buprenorphine to try to maximize the activation of as many opioid receptors as possible. Additionally, the use of other adjunctive medications with proven efficacy for opioid withdrawal, such as clonidine, is recommended. (Weimer 2023).
In cases in which withdrawal remains severe, there is case report-level evidence for the use of ketamine although its use may be institutionally limited to specific care settings (e.g., ED, SDU ICU) or specific clinical teams (Christian 2023, Hailozian 2022). In Dr. Weimer’s expert opinion, other options include using full agonist opioids and benzodiazepines in the short term to improve symptoms.
Listeners will understand how buprenorphine and methadone initiations have changed to adapt to a more potent and variable drug supply
After listening to this episode listeners will…
Dr. Weimer reports no relevant financial disclosures. The Curbsiders report no relevant financial disclosures.
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.https://thecurbsiders.com/addiction October 17, 2023.
Producers: Shawn Cohen MD, Kenneth Morford MD
Writer: Carolyn Chan MD MHS
Show Notes: Shawn Cohen MD
Infographic and Cover Art: Kenneth Morford MD
Hosts: Carolyn Chan MD. MHS Shawn Cohen MD, Natalie Stahl MD, Kenneth Morford MD
Reviewer: Kento Sonoda MD
Showrunner: Carolyn Chan, MD, MHS
Technical Production: PodPaste
Guest: Melissa Weimer DO MCR
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