Introduction

  • 1. Between 1999-2017, ~400,000 people died from opioid overdose, which tops that of deaths from HIV in the same time period.
  • 2. Recently, treatment options for opioid use disorder (OUD) in the emergency department (ED) has been a common debate with various therapeutic regimens proposed
  • 3. Buprenorphine has emerged as a common treatment modality for MAT with many caveats to its use in the ED

Pharmacology

CategoryDetails
Dose- Day 1: 2-4 mg may titrate dose, based on control of acute withdrawal symptoms every 2 hours up to a total dose of buprenorphine 8 mg/naloxone 2 mg
- Day 2: Previous dose from day 1 if no withdrawal symptoms present; if symptoms of withdrawal present, increase day 1 dose by 4 mg. If withdrawal symptoms not relieved after >2 hours, may administer 4 mg; maximum daily dose on day 2: 16 mg daily.
Administration- Sublingual film: Administer film whole; do not cut, chew, or swallow. Place one film under the tongue until the film completely dissolves, close to the base on the left or right side. If more than one film is needed, the additional film should be placed under the tongue on the opposite side from the first film.
FormulationsBuprenorphine + Naloxone Sublingual/Buccal Films:
- Generic Buprenorphine HCl-Naloxone HCl Sublingual, Bunavail Buccal, and Suboxone Sublingual
Buprenorphine:
- Sublingual: Subutex and generic buprenorphine HCL
- Injection: Buprenex and generic buprenorphine HCL
PK/PDAbsorption
- Bioavailability- IM: ~95% ; SL: 31%
- Liquids reduces absorption 23% to 27%
Distribution
- Vd: 97 to 187 L (adults)
- Time to Peak Concentration- SL: 1.5-4 hours
Metabolism
- Hepatic: Extensive via CYP3A4;
- Metabolites: Norbuprenorphine: Active
Elimination
- Fecal: 69%
- Renal: 30%
Adverse Effects- QT prolonging (less than methadone)
- Precipitate withdrawal in presence of opioids/opiates
- Tachycardia, restlessness and agitation, nausea and vomiting
Drug Interactions and Warnings- QT prolonging medications such as fluoroquinolones (moxifloxacin), macrolides, antipsychotics, tricyclic antidepressants (TCAs)
- Strong CYP450 3A4 inhibitors: statins, amiodarone, haloperidol, macrolides, azole antifungals (fluconazole, ketoconazole), calcium channel blockers, grapefruit juice
Mechanism of ActionBuprenorphine is a partial agonist of mu-opioid receptors as well as a weak antagonist at the kappa receptors
- Has higher affinity to the Mu receptor (only child syndrome and wants all of mama Mu and not too much of daddy Kappa's attention)
- Partial agonism = "Ceiling Effect" (All bark and no bite)
- Slow dissociation (Doesn't know when to move on from his ex Kappmuphenia)

Induction Therapy in the ED

CategoryDetails
When to initiate?- Last dose of opioid/opiate ≥6-24 hours
- Moderate withdrawal (COWS ≥6-8)
First dose of sublingual (SL) buprenorphine- 2-8 mg then reassess in 1-2 h
If symptoms NOT controlled after first dose- Titrate by 2-4 mg based on Clinical Opioid Withdrawal Symptoms (COWS)
Max dose of SL buprenorphine- Day 1: 8 mg total dose
- Day 2: 16 mg as single dose

Evidence

Author, yearDesign/sample sizeIntervention & ComparisonOutcome
Srivastava, 2019RCT
N=26		- Buprenorphine
- Clonidine		Buprenorphine group were more likely to be receiving opioid agonist treatment at the 1-month mark compared with those participants who received clonidine to treat their withdrawal (P = .011)
Larochelle, 2018Observational
N=17,568		- Methadone maintenance treatment (MMT)
- Buprenorphine
- Naltrexone		As compared to naltrexone, buprenorphine treated patient was associated with decreases in both all-cause mortality (adjusted HR, 0.63) and opioid-related mortality (HR, 0.62).
D'Onofrio, 2017Observational
N=290		- ED-initiated buprenorphineED-initiated buprenorphine was associated with ↑ engagement in outpatient opioid addiction treatment programs + ↓ illicit opioid use
Gowing, 2017Cochrane review
N=3048 participants		- Buprenorphine
- Naltrexone
- Clonidine
- Methadone		Buprenorphine is more effective than clonidine for managing opioid withdrawal in terms of severity of withdrawal, duration of withdrawal treatment, and the likelihood of treatment completion
Berg, 2007Observational
N=11,019		- Buprenorphine
- Symptomatic treatment
- Placebo		Subjects who received buprenorphine were less likely to return to the same ED within 30 days for a drug-related visit (8%) compared to those who received symptomatic treatment (17%) (p<0.05).

Conclusions

References

  • Micromedex [Electronic].Greenwood Village, CO: Truven Health Analytics. Retrieved July 19, 2019 from http://www.micromedexsolutions.com/
  • Srivastava A. Can Fam Physician. 2019 May;65(5):e214-e220.
  • Gowing . Cochrane Database Syst Rev. 2017 Feb 21;2:
  • Larochelle MR. Ann Intern Med. 2018 Aug 7;169(3):137-145.
  • .D'Onofrio G. J Gen Intern Med. 2017 Jun;32(6):660-666.
  • Berg ML. Drug Alcohol Depend. 2007 Jan 12;86(2-3):239-44.
Tags: Day 1 2-4 mg Opioid Use Disorder Medication-Assisted Therapy