All Pharmacy Pearls

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

Dosing – Buprenorphine ± Naloxone

Phase Dosing
Day 12–4 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 2Previous 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 & Formulations

  • Sublingual film: administer film whole — do not cut, chew, or swallow. Place one film under the tongue, close to the base on the left or right side, until it completely dissolves. If more than one film is needed, place the additional film under the tongue on the opposite side from the first film.
  • Buprenorphine + naloxone: sublingual / buccal films (generic buprenorphine HCl–naloxone HCl sublingual, Bunavail buccal, and Suboxone sublingual).
  • Buprenorphine (alone): sublingual (Subutex and generic buprenorphine HCl); injection (Buprenex and generic buprenorphine HCl).

Pharmacokinetics / Pharmacodynamics

Parameter Value
AbsorptionBioavailability — IM: ~95%; SL: 31%. Liquids reduce absorption 23% to 27%.
DistributionVd: 97 to 187 L (adults). Time to peak concentration — SL: 1.5–4 hours.
MetabolismHepatic: extensive via CYP3A4. Metabolite: norbuprenorphine (active).
EliminationFecal: 69%. Renal: 30%.

Adverse Effects, Drug Interactions & Warnings

  • Adverse effects: QT prolonging (less than methadone); may precipitate withdrawal in the presence of opioids/opiates; tachycardia, restlessness and agitation, nausea and vomiting.
  • QT-prolonging medications such as fluoroquinolones (moxifloxacin), macrolides, antipsychotics, and tricyclic antidepressants (TCAs).
  • Strong CYP450 3A4 inhibitors: statins, amiodarone, haloperidol, macrolides, azole antifungals (fluconazole, ketoconazole), calcium channel blockers, and grapefruit juice.

How Does Buprenorphine Work?

  • Buprenorphine is a partial agonist of mu-opioid receptors as well as a weak antagonist at the kappa receptors.
  • Higher affinity for the mu receptor.
  • Partial agonism produces a “ceiling effect.”
  • Slow dissociation from the receptor.

Induction Therapy in the ED

Step Guidance
When to initiate?Last dose of opioid/opiate ≥ 6–24 hours ago. Moderate withdrawal (COWS ≥ 6–8).
First doseSublingual (SL) buprenorphine 2–8 mg, then reassess in 1–2 hours.
If symptoms NOT controlled after first doseTitrate by 2–4 mg based on the Clinical Opioid Withdrawal Scale (COWS).
Max dose of SL buprenorphineDay 1: 8 mg total dose. Day 2: 16 mg as a single dose.

Prescribing Buprenorphine — X-Waiver Provider

  • Under the Drug Addiction Treatment Act of 2000 (DATA 2000), to qualify to prescribe buprenorphine, physicians (as well as NPs and PAs) historically had to complete an 8-hour course and apply to obtain a waiver (DEA X-waiver).
  • Per the DEA, a non–X-waiver provider may administer buprenorphine if: no more than one day’s medication is administered or given to a patient at one time; treatment is not carried out for more than 72 hours; and the 72-hour period is not renewed or extended.

Evidence

Author, Year Design / Sample Size Intervention & Comparison Outcome
Srivastava, 2019RCT; N=26Buprenorphine vs. clonidineBuprenorphine 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=17,568Methadone maintenance treatment (MMT) vs. buprenorphine vs. naltrexoneAs compared to naltrexone, buprenorphine-treated patients were associated with decreases in both all-cause mortality (adjusted HR, 0.63) and opioid-related mortality (HR, 0.62).
D’Onofrio, 2017Observational; N=290ED-initiated buprenorphineED-initiated buprenorphine was associated with ↑ engagement in outpatient opioid addiction treatment programs and ↓ illicit opioid use.
Gowing, 2017Cochrane review; N=3,048 participantsBuprenorphine vs. naltrexone vs. clonidine vs. methadoneBuprenorphine 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=11,019Buprenorphine vs. symptomatic treatment vs. placeboSubjects 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

  • Buprenorphine has emerged as a common medication-assisted therapy option for opioid use disorder in the emergency department, where its partial mu-opioid agonism with a ceiling effect and slow receptor dissociation underlie its favorable profile.
  • Because buprenorphine can precipitate withdrawal in the presence of opioids, ED induction should be COWS-guided—initiated only once the patient is in at least moderate withdrawal (COWS ≥ 6–8, last opioid dose ≥ 6–24 hours prior)—and then titrated to symptom control.
  • The reviewed evidence supports ED-initiated buprenorphine, which has been associated with greater engagement in outpatient opioid treatment and reduced illicit opioid use, lower mortality, more effective withdrawal management than clonidine, and fewer drug-related return ED visits.
  • Linkage to ongoing care is central: the goal of ED induction is to bridge patients into continued outpatient opioid agonist treatment, while remaining mindful of prescribing considerations and the drug-interaction and adverse-effect caveats noted above.

References

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Micromedex [Electronic].Greenwood Village, CO: Truven Health Analytics. Retrieved July 19, 2019 from http://www.micromedexsolutions.com/
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Srivastava A. Can Fam Physician. 2019 May;65(5):e214-e220.
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Gowing . Cochrane Database Syst Rev. 2017 Feb 21;2:
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Larochelle MR. Ann Intern Med. 2018 Aug 7;169(3):137-145.
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.D'Onofrio G. J Gen Intern Med. 2017 Jun;32(6):660-666.
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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

Source PDF

Buprenorphine for MAT. Pharmacy friday.jlp3(1).pdf