CONTENTS

• Rapid Reference 🚀
• All hands on deck
• Buprenorphine basics
• Buprenorphine induction
• Acute pain in a patient on chronic buprenorphine
• Podcast
• Questions & discussion
• Pitfalls

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rapid reference

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all hands on deck

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Between 1999-2017, ~400,000 people died from opioid overdose.  That’s over half the number of Americans who have ever died from HIV.

It is increasingly clear that opioid use disorder (OUD) is a chronic psychological disease involving persistent changes in neurobiology.  Abstinence programs have been shown to fail, because cravings persist for months after the physical symptoms of withdrawal abate.  Thus, patients with OUD require ongoing medical and psychiatric care in the same manner as patients with severe depression.  To resolve the opioid crisis, we must invite patients with OUD into the house of medicine and treat them compassionately and effectively.

Addiction medicine specialists are leading the charge against OUD, but that’s not enough.  Patients with OUD interact with practitioners across the entire healthcare system (e.g. emergency physicians, intensivists, and hospitalists).  Everyone managing these patients should be prepared to treat this disorder.  Ideally, therapeutic strategies for OUD should be integrated across healthcare networks (not merely addiction specialists working in silos).

In critical care, we often focus on high-tech, invasive therapies.  More mundane things may be overlooked.  OUD is often overlooked because these patients generally won’t die from opioid intoxication within our walls.  Furthermore, if an OUD patient goes home and overdoses, this will be blamed on the patient (whereas if a patient with coronary disease went home and died, we would feel responsible).  The unfortunate truth is that OUD is a pervasive and lethal disease, deserving our respect as much coronary disease.  The good news is that new therapies have improved the outlook in OUD, so ongoing efforts to treat can be very effective.

Recently, medication-assisted therapy with buprenorphine has emerged as a preferred therapy for OUD.(30616926)  Especially in rural areas, this may be the only logistically feasible strategy for providing medical therapy to these patients.  Buprenorphine is supported by a strong evidence base demonstrating harm reduction and improved adherence to therapy.

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buprenorphine basics

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understanding buprenorphine/naloxone combination products

• Buprenorphine is typically delivered in sublingual strips or tablets which also contain naloxone.
• Naloxone isn’t absorbed, but is included merely to avoid tampering with the strips.
• For patients in the hospital under supervised treatment, it is equally effective to provide buprenorphine alone.
• The best way to think about these products is simply as a safe delivery device to provide the patient buprenorphine.

buprenorphine pharmacodynamics

• Buprenorphine has a high affinity for the mu opioid receptor, but it is a partial agonist. This makes it a perfect drug to use for opioid use disorder:
  • a) If the patient takes heroin while on buprenorphine, the buprenorphine will tend to block the effect of heroin (thereby affording some protection against respiratory arrest).
  • b) If the patient takes an excessive dose of buprenorphine, they won’t have a respiratory arrest (buprenorphine is a partial agonist, giving it a ceiling effect).
• Buprenorphine is an antagonist of the kappa opioid receptor, which may give it antidepressant properties.(30500943)

buprenorphine pharmacokinetics

• Buprenorphine is generally provided as a sublingual film with peak serum levels 1-2 hours after administration. It’s sublingual bioavailability is ~50%.
• Buprenorphine is cleared by the CYP3A4 enzyme system in the liver with a half-life of 24-60 hours.(30500943)
  • Drugs that interact with CYP3A4 may affect buprenorphine levels (table below).
  • Buprenorphine doesn’t seem to affect the levels of other medications.(12756210)
• Hepatic metabolism occurs via glucuronidation, which is fairly well preserved in cirrhosis.(10451781)
• Dose adjustment isn’t needed for renal dysfunction.(22809652)

safety

• Buprenorphine is a partial agonist, which by itself appears unable to cause respiratory arrest. Overall, buprenorphine is vastly safer than most other opioids (which are full-strength mu-agonists).  For example, buprenorphine may be used intentionally to treat respiratory suppression induced by other opioids.
• Respiratory suppression may occur if buprenorphine is given in combination with other agents (e.g. benzodiazepines).

diversion/abuse potential

• Combined buprenorphine/naloxone seems to have a low abuse potential. For example, if it were dissolved and injected the naloxone would cause opioid withdrawal.
• Buprenorphine/naloxone may be diverted to the street and sold illicitly. However, illicit buprenorphine/naloxone seems to be used to manage opioid withdrawal (rather than being used recreationally to get high).  This illicit use of buprenorphine/naloxone isn’t necessarily bad.  It’s safer for someone with opioid use disorder to use buprenorphine to avoid withdrawal, instead of using IV heroin or fentanyl.

pregnancy

• Ongoing opioid use disorder poses a huge risk to both mother and fetus.
• Buprenorphine is a preferred therapy for opioid use disorder throughout both pregnancy and breastfeeding.(30355476)  The MOTHER trial showed that buprenorphine use in pregnancy causes less neonatal abstinence syndrome compared to methadone.(21142534)
• Pregnant and nursing women can be treated similarly to other women: (32234267)  📄
  • (1) Buprenorphine with naloxone is safe in pregnancy.  Previous concerns regarding naloxone are unfounded.
  • (2) Buprenorphine should be continued during breastfeeding (drug transfer is minimal).

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buprenorphine initiation

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Patients commonly present following drug intoxication (sometimes requiring intubation).  Traditionally we would send these patients home following evaluation for suicidality.  However, it’s becoming increasingly clear that these patients may also require screening and therapy for OUD.  Simply returning a patient to the community to continue illicit opioid use isn’t providing meaningful treatment.

candidacy for buprenorphine

Indications for treatment:

• Patient with opioid use disorder who is interested in treatment.
• Patient should be in withdrawal (or impending withdrawal).

Contraindications:  The only absolute contraindication to buprenorphine use is allergy to buprenorphine.  However,  some patients may benefit most from an alternative approach (e.g., admission for simultaneous management of multiple problems, methadone clinic, or expert consultation).

• Hepatic failure.
• Methadone use (especially if patients are planning to return to methadone therapy).
• Other active neurologic problems (e.g., multifactorial delirium, simultaneous alcohol intoxication or alcohol withdrawal).
• Other active medical problems (e.g., pneumonia, respiratory failure).
• Severe polysubstance abuse:  Buprenorphine could theoretically synergize with alcohol or benzodiazepines to increase the risk of respiratory suppression.  However, this may be the lesser evil, compared to ongoing uncontrolled OUD.

timing of buprenorphine initiation

• Buprenorphine is a partial agonist:
  • If buprenorphine is started while the patient still has a considerable amount of other opioids on board, it may precipitate opioid withdrawal.
  • If buprenorphine is started while the patient has some withdrawal symptoms, the buprenorphine will make the patient feel better.
• Buprenorphine initiation should be delayed until the patient is experiencing signs and symptoms of mild-moderate opioid withdrawal. This is generally defined using a COWS score above seven.🧮  This should include at least one objective sign of opioid withdrawal.(30616926)  If it’s unclear whether the patient is in withdrawal, watchful waiting should reveal this.
• Patients taking longer acting opioids are at greater risk of induced withdrawal.  As a general rule of thumb:(32234267)  📄
  • Patients using short-acting opioids (e.g., heroin) should wait >8-12 hours since last use
  • Patients using extended-release opioids (e.g., oxycontin, MS-contin) should wait >24 hours since last use
  • Patients on methadone should wait >72 hours after last use

initiation:  day #1

• Buprenorphine has a fairly rapid absorption (1-2 hours) and a long half-life.  Therefore, multiple doses will accumulate over time.
• The starting dose is generally low (~4 mg). However, for patients with more severe withdrawal (e.g. COWS >12), an initial dose of 8 mg may be given.
• The first dose should improve symptoms of withdrawal.  If symptoms persist, additional doses should be administered up to a maximal cumulative dose of 32 mg.(30616926)  Most patients will achieve full symptomatic relief at a total dose of 8-16 mg.
• Administration of additional doses may be considered even after symptoms resolve (up to a total of 24-32 mg). This may be performed selectively, with the following goals:
  • Prevent residual withdrawal symptoms or cravings in heavy users.
  • Extend the duration of action up to ~72 hours, for patients with difficulty obtaining a follow-up prescription (more on this below).

what if buprenorphine causes clinical worsening?

• Buprenorphine can cause isolated nausea.  This may simply be treated with ondansetron.
• Rarely, buprenorphine may cause exacerbation of withdrawal symptoms. This suggests the presence of significant residual opioid.  Optimal treatment here is controversial.  The following options may be considered:
  • (1) Additional buprenorphine may overcome residual opioids, causing improvement in withdrawal symptoms (up to 32 mg).
  • (2) Buprenorphine therapy may be held to allow for residual opioid to dissipate.  Additional doses may be provided after several hours.  In the interim, non-opioid therapies may be used to control symptoms, for example:
    • Clonidine or midazolam for anxiety.
    • Ondansetron or prochlorperazine for nausea/vomiting.
    • Loperamide for diarrhea.
    • Acetaminophen and NSAIDs for pain (if no renal dysfunction); low-dose ketamine for refractory pain.

maintenance therapy

• The initial maintenance dose is usually ~16 mg/day.
• For patients who required higher doses initially for symptomatic relief, a higher maintenance dose may be required.

discharge prescription

• Ideally follow-up should be arranged prior to discharge, but this may not always be possible (e.g. over weekends).
  • Buprenorphine treatment practitioners can be located here.
• The patient should ideally be discharged with enough buprenorphine to last until they can obtain outpatient follow-up. However, outpatient buprenorphine can be prescribed only by a provider with an X-waiver.
  • Usual prescription is for 16 mg sublingual buprenorphine/naloxone daily for 3-7 days until a follow-up appointment (if known).(30616926)
• If no providers are available with an X-waiver, an alternative approach is to gradually provide the patient with a large cumulative dose of buprenorphine in the hospital (e.g. 32 mg). Since buprenorphine has a ceiling effect, this won’t increase the physiologic effect of the drug.  However, providing a large total dose of buprenorphine will extend the duration of drug effect (e.g. ~3 days).(30616926)  This may provide the patient with enough time to seek outpatient follow-up.  If they are unable to obtain follow-up within this time, they may return to the hospital for additional buprenorphine.
• Patients should be counseled to avoid combining buprenorphine with benzodiazepine or alcohol to avoid excessive sedation.
• Patients should be advised to return to the emergency department if unable to establish outpatient treatment.

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acute pain management in a patient on chronic buprenorphine

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Occasional patients may be on buprenorphine solely for the management of chronic pain (without any history of opioid use disorder).  Discontinuation of buprenorphine in these (rare) patients is safer, as it does not incur a risk of recrudescent opioid use disorder.(32061413)  The following discussion is focused on patients who are on buprenorphine for opioid use disorder.

With increasing success of buprenorphine in opioid use disorder, it is increasingly common to encounter patients on chronic maintenance buprenorphine who are admitted for an unrelated issue.  Generally, this is straightforward:  just continue the buprenorphine.  Any practitioner can prescribe buprenorphine to patients admitted to the hospital (an X-waiver is not required).  However, buprenorphine therapy is more complicated if the patient is suffering from acute pain.

general principles

• (1) Buprenorphine is an effective analgesic, with potency roughly thirty times higher than morphine.(30500943)  Buprenorphine has a greater affinity for the mu opioid receptor than other opioids.  Therefore, buprenorphine could block the ability to use other opioids for breakthrough pain.  However, this seems to occur only at higher doses of buprenorphine (>8-12 mg daily dose).  At lower buprenorphine doses, there may be synergistic analgesia between buprenorphine and other opioids.(30500943, 29452378)
• (2) Don't stop the buprenorphine.  Discontinuation of buprenorphine and exposure to full opioid agonists increases the risk of relapsing opioid use disorder.(32827109)  In many cases, the risk posed by relapsed opioid use disorder is greater the risk of the acute medical problem being managed.  Thus, discontinuation of buprenorphine carries a substantial potential for harm and should be avoided.
• (3) These patients are opioid-tolerant.  No matter whether the buprenorphine is continued, up-titrated, down-titrated, or stopped, the patients will still have opioid tolerance – so opioid analgesia will inevitably be less effective for them.  Thus, the cornerstone of management is often multimodal, non-opioid analgesia (more on this below).

non-opioid analgesia

• A multimodal approach combining several non-opioid medications is the most effective.📖
• Local measures may be helpful (e.g., nerve blocks or lidocaine patches).
• Scheduled acetaminophen (e.g. 1 gram orally q6hr) should be used, unless contraindicated.
• A pain-dose ketamine infusion (e.g. 0.15-0.3 mg/kg/hr) augments analgesia, with a minimal side-effect profile.
• Oral clonidine or IV dexmedetomidine will provide analgesia, while synergizing with ketamine.
• NSAIDs may be used in patients with low risk of acute kidney injury.
• Gabapentin and IV lidocaine may be some other options.

opioid management strategy for most patients

• Begin by continuing the patient's home dose of buprenorphine.  However, for analgesic efficacy, buprenorphine should be given more frequently.  Thus, the patient’s usual daily dose should be divided and given q6hr-q8hr.
• If the patient has refractory pain (despite non-opioid analgesics), then two additional options exist:
  • (a) The total daily dose of buprenorphine may be increased, up to a total daily dose of 32 mg divided q6hr-q8hr.(32827109)  This may be done either with an increase in the scheduled dose, or with the use of additional PRN buprenorphine doses (e.g., 2-8 mg sublingual).  This may be preferable to the addition of full agonists.(32234267)  📄
  • (b) Alternatively, breakthrough pain may be treated with full opioid agonists (e.g., morphine, fentanyl). Higher doses than usual will be required.(32827109)

opioid management strategy for exceptionally severe pain

• Continuation of buprenorphine has be shown to be adequate in patients undergoing C-section or vaginal delivery, so most medical/surgical patients could likely be managed with buprenorphine continuation or dose-escalation (as described in the section above).(32827109)  However, in some exceptional situations where patients are exposed to extremely high levels of pain, this might not be adequate (e.g., major spine surgery).(32061413)  The approach to this scenario remains controversial.
• One strategy is that if the patient is on >12 mg buprenorphine daily, consider reducing the cumulative daily dose to 8-12 mg.(30500943, 29452378)  This should be provided in divided doses q6hr-q8hr.  Additional doses of full mu opioid agonist may be added on top of the buprenorphine, to control breakthrough pain.  When pain is resolving, increase the buprenorphine dose back to the original maintenance dose.
• Consider consulting anesthesia/pain specialists in situations of severe pain that require a reduction in buprenorphine dose.

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questions & discussion

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To keep this page small and fast, questions & discussion about this post can be found on another page here.

• For patients with opioid use disorder, in addition to treating their acute problem, consider initiation of medication-assisted therapy.  Simply patching up the acute problem and sending them home won't fix the underlying issue.
• Make sure patients are in withdrawal before initiation of buprenorphine (otherwise it may induce withdrawal and make patients feel worse).
• Buprenorphine isn't for everyone – review the list of relative contraindications before initiation.  Consider expert consultation for more complex cases (e.g. patients abusing methadone or patients with complex polysubstance abuse).
• For patients on chronic buprenorphine and acute pain, don't stop the buprenorphine.  The key here is addition of multimodal non-opioid therapies (acetaminophen, ketamine, clonidine/dexmedetomidine, gabapentin).

Guide to emoji hyperlinks 

•  = Link to online calculator.
•  = Link to Medscape monograph about a drug.
•  = Link to IBCC section about a drug.
•  = Link to IBCC section covering that topic.
•  = Link to FOAMed site with related information.
• 📄 = Link to open-access journal article.
•  = Link to supplemental media.

Going further 

• FREE MAT Waiver Training Online here.  This runs off of an iPhone, so you can get waivered while working out, or on the couch.
• AAEM White Paper consensus on treatment of opioid use disorder by Strayer RJ et al:  Free PDF here.
• Institutional guidelines
  • Yale: ED-initiated Buprenorphine
  • Vermont buprenorphine practice guidelines
  • Ed-bridge.org
• Podcasts
  • EM:RAP has a free, absolutely epic podcast with Rubin Strayer here.
  • FOAMcast (by Lauren Westafer and Jeremy Faust) has a great podcast on this here
• Blogs & articles
  • Buprenorphine: Where do we stand?  (David Cisewski, emDocs)
  • Rx Pad: Reducing relapses through opioid maintenance (Karen Serrano and Christina Shenvi, EP Monthly)
  • Do patients with opioid dependence benefit from buprenorphine/naloxone treatment initiation in the emergency department?  (Jonathan Gravel, RebelEM)