Buprenorphine in the Intensive Care Unit: Commentary on the Unanswered Questions

Abstract

The removal of the X-waiver in the Mainstreaming Addiction Treatment (MAT) Act of 2023 has substantial implications for buprenorphine prescribing as one of the options to treat opioid use disorder. The purpose of this commentary is to discuss the unanswered questions regarding buprenorphine in the ICU including how the passage of the MAT Act will affect ICU providers, which patients should receive buprenorphine, what is the most appropriate route of administration and dose of buprenorphine, what medications interact with buprenorphine, and how can transitions of care be optimized for these patients.

Introduction

A recent study found that only one in five adults with past-year opioid use disorder (OUD) received medications for OUD (MOUD), despite strong evidence that they increase retention in treatment and decrease morbidity and mortality.¹ With the removal of the X-waiver in the Mainstreaming Addiction Treatment (MAT) Act of 2023,² a Drug Enforcement Administration (DEA) administrator has estimated that the number of potential buprenorphine prescribers will increase from 130,000 to 1.8 million,³ and thus more patients on buprenorphine are likely to be seen in critical care settings. Since there is a lack of guidance regarding the management of buprenorphine in critically ill patients,⁴ this commentary discusses the unanswered questions regarding buprenorphine in the ICU and provides guidance for future investigations.

How will the passage of the MAT Act of 2023 affect the number of buprenorphine-treated patients admitted to ICUs?

When the 117^th United States Congress passed the MAT Act, Section 1262 of the Consolidated Appropriations Act, on December 29, 2022, the X-waiver requirement for prescribing buprenorphine to treat OUD was removed. Although it is unknown how the passage of the MAT Act and the removal of the X-waiver will impact critical care providers, it is likely that there will be an increase in the number of patients on buprenorphine admitted to the ICU. According to recent data, there were approximately 80,000 adult critical care beds in 2021 with 5.7 million patient admissions annually.^5,6 In a study of the Longitudinal Prescription (IQVIA LRx) database from 2009 through 2018, annual buprenorphine treatment per 1,000 population increased from 1.97 to 4.43, further supporting an increase in patient encounters as time goes on.⁷ The anticipated increase in the number of buprenorphine-treated patients admitted to the ICU presents an opportunity for pharmacists and other members of the care team to develop and implement screening procedures that increase the likelihood of promptly identifying such patients and increase in the percentage of patients receiving timely, uninterrupted continuation of buprenorphine in the ICU and throughout their hospital stay.

Which patients in the ICU should receive their premorbid buprenorphine?

According to multiple organizations, most patients should have their home buprenorphine maintained while in the ICU. Although the most robust evidence would come from randomized controlled trials, the majority of evidence supporting these recommendations comes from case reports and retrospective studies.^8,9

When patients taking MOUD are hospitalized, Substance Abuse and Mental Health Services Administration (SAMHSA) states that it is “essential for the patient to continue receiving” therapy while recognizing the need to balance other medical concerns.¹⁰ The Society of Hospital Medicine has compiled a consensus statement that recommends continuation of buprenorphine during hospitalization.¹¹ The Society further recommends that patients with OUD who are not taking MOUD be offered buprenorphine or methadone.¹¹ Similarly, the National Academy of Medicine encourages all physicians to screen for and treat OUD,¹² and a multi-society working group on OUD recommends continuation of buprenorphine even during the perioperative period as untreated OUD can lead to premature discharge, worsening of other medical conditions, readmission, relapse, and overdose.¹

Despite these recommendations, a recent evaluation of MOUD prescribing patterns in the ICU setting from 2016 to 2020 showed that only 19% (20,508) of 108,189 patients with a history of OUD received MOUD.¹³ Similarly, a survey of providers from 58 ICUs in the United States showed that only one (2%) reported a protocol for the management of patients on MOUD, and just 36% supplied patients with resources to manage OUD upon hospital discharge.¹⁴

However, there are clinical scenarios that might warrant a temporary discontinuation or decrease of an ICU patient’s home buprenorphine dose. As buprenorphine is primarily metabolized in the liver by CYP3A4 enzymes, patients with severe hepatic impairment may require dose reductions or cautious withholding.¹⁵ Similarly, a decreased dose in the setting of impaired mental status may be prudent to minimize the risk of excessive sedation, which could complicate diagnostic efforts and impact cognitive outcomes.¹⁶ However, iatrogencially inducing withdrawal can also further confuse the clinical picture.

Every ICU should develop a systematic, protocolized approach for the continuation of premorbid buprenorphine. Protocols should default to buprenorphine continuation in the absence of well-defined exceptions, recognizing that there may be patient- and institutional-specific factors that affect both the decision to continue therapy and the choice of formulation. For such issues, consultation with pain and addiction consult services is recommended.

What is the most appropriate route of administration for buprenorphine in the ICU?

Buprenorphine comes in many formulations with product-specific bioavailability, including transdermal patches, buccal films, sublingual tablets, intravenous and intramuscular solutions, and extended release injectables. For patients previously maintained on formulations with long half-lives, such as the weekly and monthly extended-release subcutaneous (SC) injections, it is possible that they will not need re-dosing of their buprenorphine while hospitalized. But if they do need re-dosing while hospitalized, their home buprenorphine formulation may not be available on a hospital’s formulary. Unfortunately, there are no studies evaluating the most appropriate product-to-product dosing conversions in critically ill patients.

In the community, sublingual buprenorphine is the most utilized formulation. But in critically ill patients, sublingual absorption can prove challenging. For example, encephalopathy, mechanical ventilation and sedation, and xerostomia can hinder the sustained contact with the sublingual tissue required for proper absorption. Additionally, altered microcirculation may result in reduced bioavailability following administration.¹⁶ Despite these challenges, sublingual administration may still be feasible. In a retrospective study of non-opioid dependent ICU patients receiving sublingual buprenorphine as a weaning strategy from intravenous opioid administration, the researchers found similar pain management outcomes and median doses of opioid utilization (when converted to morphine milligram equivalents) between the groups, irrespective of ventilator use.¹⁷

To bypass some of the challenges of sublingual administration in critically ill patients, many addiction physicians temporarily turn towards intravenous (IV) formulations until their patients are more stable. The injection is supplied in 1 mL glass ampules with a concentration of 0.3 mg/mL. However, injectable buprenorphine product has not been studied in critically ill patients, nor is it FDA approved for OUD.

The various formulations and possible dosing regimens available for buprenorphine may complicate the decision-making process when a formulation used in the outpatient setting is not available in a particular ICU, or when patient-specific considerations necessitate a change to an alternate formulation. Similarly, there are patient- and institutional-specific considerations that must be considered when choosing the most appropriate formulation and route of administration for buprenorphine induction in the ICU. The reader is referred to recent reviews discussing formulations of buprenorphine available in the US along with considerations related to their use.^8,18

What is the most appropriate dosing regimen for buprenorphine in the ICU?

Ideally, patients already taking buprenorphine would be maintained on their home dose when admitted to the ICU. Buprenorphine has a pharmacokinetic profile that includes a large volume of distribution (log P of approximately 5), high protein binding of approximately 96%, relevant first-pass metabolism (sublingual or buccal administration), a long elimination half-life (24–48 hours), and metabolites with unclear in vivo activity.¹⁹ This profile allows for a rapid onset of action, particularly with isolated bolus doses given by IV injection, as well as a variable duration of effect, depending on the number of intermittent doses administered until a scheduled regimen attains steady-state conditions. There is a general relationship between plasma buprenorphine concentrations and brain mu-receptor occupancy for OUD, but no therapeutic window has been defined and drug monitoring is not widely available so dosing is guided by clinical response.²⁰ Adjustment of buprenorphine dosing is guided by clinical response, not by quantitative concentrations, which can be challenging in altered patients.

For patients who are not yet on buprenorphine or whose buprenorphine was discontinued, there are various induction strategies. Traditional inductions did not begin until all other opioids were held and a patient was in opioid withdrawal, and then a total of 8–32 mg/day was typically given. But in the ICU, where up to 50% of patients experience moderate to severe pain, it can be impractical to require a “washout” period devoid of opioid pain medications. In such situations, many addiction physicians recommend buprenorphine induction via a microinduction/cross-tapering approach.²¹ In a retrospective study published in abstract form, cross-tapering with buprenorphine (150 mcg every 6 hours titrated to ≥4 mg/day over five days) in mechanically ventilated patients on continuous opioid infusions was safe and associated with a reduction in opioid exposure.²¹ Until a patient is transitioned onto buprenorphine, other agonists, including methadone, can be utilized. And if methadone is working well for the patient, there is no need to rush the transition to buprenorphine. Methadone is also a highly effective form of MOUD, although it comes with its own unique considerations and challenges.

Patients receiving buprenorphine prior to ICU admission should continue their outpatient treatment regimen when feasible given the challenges in converting to different formulations with possibly different dosing schedules. For patients being considered for buprenorphine induction in the ICU, protocols should be developed that provide preferred dosing regimens based on product-specific formulations available in the institution. There is insufficient evidence to recommend a preferred approach for all possible clinical scenarios, but literature is available that provides more details on different formulations and dosing regimens of buprenorphine.^8,18

Which medications affect buprenorphine’s pharmacokinetics and pharmacodynamics?

As buprenorphine is metabolized by cytochrome P450 (CYP) 3A4, other medications affecting this pathway may alter buprenorphine’s pharmacokinetics and pharmacodynamics.¹⁹ Additionally, despite buprenorphine’s reported ceiling effect for respiratory depression, buprenorphine can be sedating in patients receiving other central nervous system depressants and/or affect adequate ventilation in patients with significant comorbidities.

Although there is evidence that buprenorphine is a partial mu-receptor agonist with full clinical analgesic efficacy,¹⁹ critically ill patients on buprenorphine often still experience acute pain, and it can be challenging to find pain regimens that work due to a cross-tolerance to other opioids.²² Although there are recommendations around buprenorphine dosing adjustments, preferential use of opioid agonists with higher affinities, and incorporation of non-opioid adjuncts (including acetaminophen, gabapentin, non-steroidal anti-inflammatory drugs, duloxetine, dexmedetomidine, clonidine, ketamine, and lidocaine), most of this information is based on mechanistic appeal, anecdotal information, retrospective studies, or extrapolation from other patient populations. Thus, additional research is needed regarding analgesia in critically ill patients receiving buprenorphine. Non-pharmacologic approaches should also be considered, as they are generally understudied despite their overall low risk.

How can appropriate transitions of care be provided for patients treated with buprenorphine?

Ideally, healthcare systems and case managers can help facilitate the transition of addiction care from the inpatient to the outpatient setting, as continuation of MOUD is an extremely important component of the chain of survival for a disease with a high mortality rate. Buprenorphine should be continued after hospital discharge, whether the patient is going to a skilled nursing facility, residential treatment facility, carceral institution, or home. Occasionally, such facilities do not carry buprenorphine, even though it is considered a violation of the Americans with Disabilities Act. If a patient is going home, a buprenorphine prescription should be provided as a bridge until their OUD care can be transitioned to an outpatient provider. If the patient does not yet have an outpatient buprenorphine provider, a list of local outpatient MOUD providers should be provided, and case management or peer support can help ensure the linkage to care. As some insurance plans require prior-authorization for the mono-product, it is usually advisable to instead provide the equivalent combo-product of buprenorphine/naloxone.

Conclusions

Protocols should be developed around the use of buprenorphine in the ICU setting, both in terms of starting and continuing patients on buprenorphine. Such protocols should address route and dosing considerations, factors that may alter buprenorphine pharmacokinetics/pharmacodynamics, and issues related to transitions of care. More research is needed to establish comprehensive guidelines for buprenorphine management in critical care settings.