#20 Extending Knowledge of LAI Buprenorphine with Dr. Ken Lee

August 31, 2023 | By Carolyn Chan

Audio

Video

Learn about long-acting injectable (LAI) buprenorphine for the treatment of opioid use disorder with Dr. Ken Lee, an addiction medicine provider in Canada. We go over the basics of using LAI buprenorphine, tips and tricks for troubleshooting with patients as well as newer protocols that Dr. Lee and his colleagues use.  

Claim free CME for this episode at curbsiders.vcuhealth.org!

By listening to this episode and  completing CME, this can be used to count towards the new DEA 8-hr requirement on substance use disorders education.

Episodes | Subscribe | Spotify | Swag! | iTunes | CurbsidersAddictionMed@gmail.com | Free CME!

Production Partner: ACAAM

The Curbsiders Addiction Medicine are proud to partner with  The American College of Addiction Medicine (ACAAM) to bring you this mini-series.  ACAAM is the proud home for academic addiction medicine faculty and trainees and is dedicated to training and supporting the next generation of academic addiction medicine leaders. Visit their website at acaam.org to learn more about their organization.

Show Segments

• Intro, disclaimer, guest bio – 1:58
• Guest one-liner – 4:15
• Case from Kashlak; Definitions – 5:27
• Injectable MOUD – 6:14
• Plasma levels of buprenorphine – 7:14
• Relative contraindications to LAI buprenorphine- 8:51
• Tips for Patient Counseling – 12:28
• Starting LAI buprenorphine – 16:01
• Side effects of LAI bup – 25:45
• Administering LAI bup – 29:06
• Dosing Interval – 31:53
• Other LAI considerations – 42:19
• Take home points – 47:24
• Outro – 49:18

LAI Buprenorphine Pearls

1. Long-acting injectable (LAI) buprenorphine is approved for the treatment of opioid use disorder.
2. LAI Buprenorphine is available in two strengths in the U.S. – 300 mg and 100 mg.
3. The dosing frequency of LAI buprenorphine is ideally every 28 days but can be given every 26-42 days.
4. It takes 4 – 6 months of LAI buprenorphine to reach a steady state. Some individuals may have breakthrough cravings, particularly after their first dose. It is ok to use supplemental SL buprenorphine as needed, particularly near the end of the month.
5. To start someone on 300mg of LAI buprenorphine, the general rule of thumb is that they should be able to tolerate at least 8 mg of SL buprenorphine, to decrease their risk of adverse effects such as sedation and precipitated withdrawal from the injection.
6. For folks who are using fentanyl, LAI buprenorphine maintenance at 300 mg monthly may be preferable to using the 100mg dose for maintenance.
7. Be sure to discuss the goals of buprenorphine therapy when deciding what formulation makes the most sense for patients – abstinence vs. overdose prevention vs. decrease in use.
8. Give the LAI buprenorphine injection in 10 seconds, after icing the site to reduce any discomfort associated with the injection.

LAI Buprenorphine – Show Notes

Injectable Medications for the Treatment of Opioid Use Disorder

There are multiple medications available for the treatment of opioid use disorder (OUD) such as methadone PO, IM naltrexone, and buprenorphine-naloxone SL. In the United States (U.S.) there are two long-acting injectable (LAI) medications FDA-approved to treat OUD, which include an LAI buprenorphine and an LAI naltrexone. In this episode, we focus on LAI buprenorphine. 

LAI Buprenorphine Dosing

Notably, there are 2-formulations of LAI buprenorphine in the US that the FDA has approved, Sublocade (approved in 2017) and Brixadi (recently approved in May 2023, and will not be available until September 2023). We will focus on the currently available LAI buprenorphine formulation that was approved in 2017. The 2017-approved LAI Buprenorphine has 2 doses; 300mg and 100mg. Per the traditional instructions, individuals should receive the 300mg dose for 2 months as a loading dose, and then continue 100mg monthly as a maintenance dose.  Notably, in the era of fentanyl, many individuals may require to continue on the 300mg dose monthly to achieve their treatment goals due to the high potency of fentanyl. It takes about 4-6 monthly doses to reach a steady state of LAI buprenorphine.

When to consider LAI Buprenorphine

Consider the following patients for LAI buprenorphine: 

• Has a diagnosis of opioid use disorder
• Patients who have challenges taking medication daily
• Patients who have a preference for an LAI medication
• Patients who have not met their treatment goal on their current MOUD

Buprenorphine Pharmacokinetics 

Dr. Lee reminds us that with SL buprenorphine, you can achieve approximately a buprenorphine plasma level of 2-3ng/mL depending on the dose, and the maximum dose we can give is 32 mg (although 16 mg-24 mg is the recommended dose by the FDA)(Granade 2023).  With LAI buprenorphine, an individual can achieve a buprenorphine plasma concentration of 3.2ng/mL with the 100 mg maintenance dose and 6.5mg with the 300 mg dosing (Haight 2019). With an LAI buprenorphine, an individual can likely achieve a higher level of plasma of buprenorphine than with the SL formulations.

In a recent study, they provided opioid-tolerant and opioid-naive patients with buprenorphine and targeted their buprenorphine plasma levels to be either 1.0, 2.0, or 5.0 ng/mL. They then provided these individuals with increasing doses of IV fentanyl and measured their isohypercapnic minute ventilation as well as the frequency of episodes of apnea.  The IV fentanyl appeared to have a lesser impact on individuals’ minute ventilation in those with higher buprenorphine concentrations in a dose-dependent manner. This effect was particularly evident in the opioid-tolerant group (Moss, 2022). 

Relative contraindications to LAI buprenorphine

Pregnancy is a relative contraindication to LAI buprenorphine, though this is largely due to a lack of evidence. In Dr. Lee’s expert opinion, if an individual is already on LAI buprenorphine, there is the potential to destabilize their OUD, which could be riskier to the patient than continuing the medication. He recommends engaging the pregnant person in shared decision-making on whether to continue the LAI or switch to a different MOUD. There are case reports describing the use of LAI buprenorphine in pregnancy (Towers 2020).

Other relative contraindications that are discussed by the manufacturers include liver disease and end-stage renal disease. In Dr. Lee’s opinion, he will continue to use LAI buprenorphine in individuals with liver disease who have been able to tolerate buprenorphine. For individuals on hemodialysis, in Dr. Lee’s experience, he has used an LAI buprenorphine maintenance dose of 100mg and reports that the patient has tolerated it well. 

Tips for counseling patients

Dr. Lee recommends discussing a few different features of LAI buprenorphine when considering this medication with patients. One of these is the potential convenience of monthly dosing, in comparison to daily dosing at a methadone clinic or remembering to take a daily medication with sublingual films or tablets of buprenorphine.  

Another important topic when considering this medication is a patient’s specific goals when it comes to opioid use disorder treatment – for example, is someone’s goal total abstinence, decreased use, or more focused on overdose prevention? In Dr. Lee’s clinical experience, individuals on the lower maintenance dose of buprenorphine at 100mg individuals may experience an incomplete euphoric blockade to smoking fentanyl, while at the higher 300 mg maintenance dose, he has observed a nearly complete euphoric blockade to smoking fentanyl.  If a patient is interested in using buprenorphine for harm reduction, they may not want the full euphoric blockade and he recommends continuing to use SL buprenorphine or using the lower dose of the LAI buprenorphine for maintenance.

There is some thought that if an individual receiving LAI buprenorphine cannot achieve euphoria while using fentanyl, then they likely have adequate overdose protection. Additional research is needed on this topic. As a result of this theory,  Dr. Lee recommends encouraging individuals who want additional overdose protection to use the higher dose of LAI buprenorphine. A recent retrospective study comparing methadone, LAI buprenorphine and SL buprenorphine showed lower rates of non-fatal overdose in the LAI buprenorphine cohort (Lee 2023).

Starting Buprenorphine

There are many ways to start buprenorphine such as the traditional start, low-dose start (e.g. micro-dosing), and high-dose inductions (e.g., macro-dosing)(Weimer 2023). The general principle is that before patients are started on LAI buprenorphine, they need to start on SL buprenorphine to demonstrate their tolerance to the medication and to be sure that they are not at risk of precipitated opioid withdrawal. The generally agreed-upon dose of SL buprenorphine that patients should tolerate before starting LAI is 8mg (package insert). In Dr. Lee’s expert opinion, individuals who are on a lower dose of SL buprenorphine may experience some sedation for the first 1-2 days after they receive the injection, and it’s important to counsel these patients.

Traditional induction: 

The traditional start for buprenorphine involves waiting until clinical opioid withdrawal occurs (COWS > 12), then giving an initial dose of 2-4 mg of SL buprenorphine. Then continue to provide additional 4 mg doses of buprenorphine on day 1 up to a maximum of 8 mg total. On day 2, can give buprenorphine up to a maximum dose of 16mg (SAMHSA TIPS 63). Now, in the era of fentanyl, most patients are maintained on doses of 16-24 mg, with some patients requiring 32 mg daily dosing to treat their OUD. 

Low-dose induction: 

There are many variations on the low dose initiation, referred to often as the Bernese Method. The basic concept behind this is that you start with very low doses of buprenorphine and gradually increase over multiple days. This allows the mu-opioid receptors to slowly become saturated with buprenorphine, avoids the need for patients to abstain from opioids, and mitigates the risk of precipitated withdrawal. There are many variations of this method using different buprenorphine products (Cohen 2022). 

High-dose induction: 

Another strategy for induction involves administering high doses of buprenorphine (>12 mg) quickly to move past the doses where patients might be at higher risk of experiencing precipitated withdrawal. This often looks like giving 8mg or 12mg to start and then quickly giving additional 8mg or 12 mg doses if any signs of withdrawal are present (Herring 2021). 

Other induction strategies: 

Dr. Lee recommends waiting 24 hours from the time an individual last smoked fentanyl and then providing 16mg of the SL buprenorphine film. He recommends a UDS to ensure there are no long-acting opioids such as methadone in a patient’s system.  In his experience, the film has more consistent absorption than tablets, so this may decrease the risk of precipitated withdrawal for some individuals. He generally pre-medicates patients before giving them buprenorphine with ondansetron 8mg and diazepam 10mg to help them through any potential side effects from starting buprenorphine. 

Counseling on side effects of LAI buprenorphine

In patients interested in switching to LAI bup, be sure to counsel on the potential side effects:

• Pain and discomfort from the injection. Try to ice the area before the injection, and warm the injection up to room temperature before administering. Place the ice pack back on to help with the post-injection burning pain which generally lasts for about 30 seconds. 
• The depot may leave a small nodule/lump in the abdomen that can last for a few months. Be sure to rotate injection sites and avoid injection in the same place if the lump is still there.
• Inject in the “sweet spot”: If it’s too superficial it can increase discomfort, and Dr. Lee recommends injecting a little bit farther from the umbilicus for better tolerance from patients. 
• Some patients experience itchiness after the injection; consider giving a dose of antihistamine.
• There is a risk of wound infection if someone tries to self-remove the buprenorphine depot.

Administering LAI buprenorphine injections: 

Dr. Lee discusses how they generally give the LAI buprenorphine injections. His recommendation is to first remove the injection ahead of time so that it can warm up to room temperature. He generally will use ice on the intended site ahead of injection. He positions the patient lying down and then pinches the intended area. He inserts the needle at a 45-degree angle and, using the appropriate injection technique, administers the medication within 10 seconds of entering the skin. 

Tip: Consider asking individuals with low BMI to sit up and lean forward to help find an area with more subcutaneous tissue for an appropriate injection site.

Injection Location

Injection sites should be rotated around the 4 quadrants of the abdomen. Dr. Lee recommends not to do the injection so low that it sits on the beltline of someone’s pants, or over a seatbelt location, as it can be irritating to the patient. 

Dosing Intervals

Ideally, the patient should receive LAI buprenorphine every 4 weeks; per the manufacturer’s instructions, they may receive it between 26 and 42 days.  If a patient comes within that time frame, the clinician can administer the injection.

Off-Label Dosing Considerations

Dr. Lee notes that for individuals with heavy fentanyl use who are receiving their first dose of LAI bup, practitioners may find they need an earlier dose of LAI bup at day 21 or provide supplemental SL buprenorphine doses before the next injection.  He notes that there are some ongoing studies looking at giving the LAI buprenorphine first two doses Q2 weeks apart, but that the results of these studies are not yet known. He clinically has tried this and has found it to be helpful, in his expert opinion. 

In Dr. Lee’s opinion, if an individual misses their next scheduled dose of LAI buprenorphine he does the following in his practice:

• At 4-6 weeks out from their last dose, he recommends patients should get their planned next dose without additional test doses for SL buprenorphine.
• At 6-12 weeks from their last dose, Dr. Lee recommends asking patients who are not at steady state LAI dosing to take a test dose of SL buprenorphine 8mg to be sure they tolerate the medication. 
• At 6-12 weeks, if they had previously reached steady state (at least 4 consecutive monthly injections), you can consider skipping a test dose of SL buprenorphine before administering LAI buprenorphine.
• At 12-18 weeks from their last dose, Dr. Lee recommends taking a history of their ongoing use and obtaining a urine drug screen.  If they have ongoing use, then give a test dose of buprenorphine. 
• At >18 weeks from their last dose, Dr. Lee will restart SL buprenorphine and then restart LAI if they are interested. He keeps them on the same prior dose that they were on.  

TIP: If a patient has missed their dose(s) of LAI buprenorphine, and the clinical scenario is unclear on whether it’s ok to give the LAI, give a test dose or restart of SL buprenorphine before administering the LAI buprenorphine. 

Other Considerations: 

Remember the drug supply is contaminated and, if an individual still describes withdrawal symptoms after 24 hours after receiving their LAI dose, consider that they could be withdrawing from another substance such as a benzodiazepine.  Consider prescribing 10mg diazepam daily for  3 days to assist with a possible benzo withdrawal component as well.

LAI Buprenorphine to help taper off SL buprenorphine

Some patients who are trying to taper off SL buprenorphine can find it challenging after tapering down to around 8mg. At that time, if an individual has challenges decreasing the dose further, consider administering a one-time 100mg LAI buprenorphine injection. Some individuals may require a second injection 4-8 weeks later of 100mg SL buprenorphine. A number of case reports have documented the success of this (Ritvo, 2021). 

Implementation Considerations

To dispense LAI buprenorphine in the U.S., a pharmacy must be REMS certified, and then the pharmacy will deliver the medication to the practice. The clinic must be able to store the medication safely in a locked box in a fridge, in a locked room. 

In Canada, it is important to consider that there are different regulations around pharmacies and dispensing of medication and options for addiction treatment, including LAI buprenorphine, and methadone regulations. Be sure to check with local regulations. 

Links

1. LAI buprenorphine product monograph

Goal

Listeners will learn how to use long-acting injectable (LAI) buprenorphine to treat substance use disorders.

Learning objectives

After listening to this episode listeners will learn how to use injectable medications LAI buprenorphine to treat substance use disorders.

1. Describe the evidence of XR-buprenorphine for OUD
2. Recognize indications, contraindications, and adverse effects of LAI for individuals with opioid use disorder
3. Describe approaches to initiate LAI-buprenorphine for opioid use disorder
4. Describe the procedure of injecting LAI-buprenorphine in a primary care office. 

Disclosures

Dr. Lee reports relevant financial disclosures for Indivior and Knight.  VCU has procedures to resolve any conflicts of interest. The Curbsiders report no relevant financial disclosures. 

Citation

Huxley-Reicher Z, Lee K, Roy, P. Chan, CA. “#20 Extending Knowledge of LAI  Buprenorphine with Dr. Ken Lee”. The Curbsiders Addiction Medicine Podcast. https://thecurbsiders.com/episode-list August 31st, 2023