II. Background

  1. Buprenorphine (with and without Naloxone) is a growing concern for misuse, abuse and diversion

III. Indications

  1. Chronic Pain Management (intravenous Buprenorphine)
  2. Opioid Addiction (e.g. Heroin addiction)
    1. Alternative to low dose Methadone
    2. Prescribing requires FDA waiver

IV. Contraindications

  1. Use caution and liver function monitoring in hepatitis

V. Mechanism

  1. Partial mu-Opioid receptor agonist
    1. Semisynthetic derivative of Thebaine
  2. Mu-receptor activation increases with dose to ceiling
    1. No further activation once max dose effect is reached
    2. Hence, unlike Heroin or Methadone, lower risk of abuse
    3. May also have less risk of respiratory depression and Overdose potential
    4. Decreases withdrawal and craving symptoms (as long as no recent Opioid use)
  3. Slowly dissociates from mu-receptors (high affinity, but lower activity)
    1. May block other Opioid binding (e.g. Heroin)
    2. May displace recently taken Opioids (e.g. Morphine, Methadone)
      1. May result in Opioid Withdrawal symptoms
  4. Adding Naloxone to Buprenorphine intended to block the "high" if Buprenorphine is crushed and injected
    1. However still with abuse risk (e.g. Zubsolv snorting, Suboxone injection)

VI. Pharmacokinetics

  1. Metabolism: Liver via P450
  2. Plasma half-life: up to 28-37 hours (sublingual), and 3 hours (IV)
  3. Routes
    1. Oral bioavailability is too low to be useful
    2. Intravenous route used for pain management
    3. Sublingual is preferred route
      1. Bioavailability: Up to 50% of IV dose
      2. Peak concentration reached 1 hour post-dose

VII. Drug Interactions

  1. P450 3A4 Inducers may decrease Buprenorphine effect
    1. Carbamazepine
    2. Phenytoin
    3. Phenobarbital
    4. Reverse Transcriptase Inhibitors
    5. Rifampin
  2. P450 3A4 Inhibitors may increase Buprenorphine effect
    1. Azole Antifungals (e.g. Ketoconazole, Fluconazole)
    2. Macrolides (e.g. Erythromycin, Azithromycin)
  3. Respiratory depressants (risk of death with combined use)
    1. Benzodiazepines
    2. Muscle relaxants (e.g. carisprodol, Cyclobenzaprine)
    3. Other Sedative-Hypnotics, other Opioids, Alcohol
  4. Other adverse effects in combination
    1. Anticholinergics (Urinary Retention, Constipation)

VIII. Efficacy: Buprenorphine compared with Methadone

  1. Low dose Methadone (<40 mg): Buprenorphine as effective
  2. High dose Methadone (>60 mg): Not as effective
  3. References
    1. Barnett (2001) Addiction 96:683-90 [PubMed]

IX. Safety

  1. Pregnancy
    1. FDA Category C
  2. Lactation
    1. Naloxone excretion into milk is unknown (and should only be used with caution)

X. Adverse Effects

  1. Constipation
  2. Urinary Retention
  3. Sedation
  4. Mild respiratory depression
  5. Opioid Withdrawal
  6. Nausea
  7. Headache

XI. Toxicity

  1. Overdose has occured when taken with Benzodiazepines

XII. Preparations

  1. Pain management
    1. Buprenorphine intravenous
    2. Buprenorphine Patch (Butrans)
      1. Patch applied once weekly
    3. Buprenorphine Buccal Film (Belbuca)
      1. Buccal film used twice daily
      2. On switching from other Opioid, wean to no more than equivalant to Morphine 30 mg/day
  2. Opioid Addiction
    1. Buprenorphine sublingual
    2. Buprenorphine with Naloxone (Suboxone, Zubsolv)
      1. Sublingual
        1. Abused despite combination with Naloxone
        2. Drug Abusers crush and snort the sublingual tabs
        3. May not appear on routine Urine Drug Screen
      2. Film (2, 4, 8 and 12 mg)
        1. Prevents snorting (but has still been misused via injection)
      3. Dosing
        1. Start: 4 mg Buprenorphine and 1mg Naloxone
        2. Titrate: Over 2 days (see dosing protocol for Buprenorphine below)
        3. Goal: 16 mg Buprenorphine and 4mg Naloxone
        4. Maximum effective dose: 32 mg Buprenorphine (no benefit above 24-32 mg daily)
    3. Buprenorphine implant (Probuphine)
      1. Implanted subdermal rods with duration of 6 months (may be replaced once in opposite arm)
      2. Indicated for patients on stable dose of Buprenorphine SL at 8 mg/day for at least 3 months
      3. Very expensive (>$800 per month)
      4. (2016) Presc Lett 23(8)
    4. Buprenorphine monthly injection (Sublocade)
      1. Once monthly Subcutaneous Injection
      2. Very expensive (>$1600 per month)
      3. Indicated for patients on stable dose of Buprenorphine SL at 8-24 mg/day for at least 1 week
      4. (2018) Presc Lett 25(3)

XIII. Dosing: Buprenorphine (prescriber must have X DEA waiver)

  1. Preparation
    1. Urine drug test
    2. Informed Consent
    3. Treatment contract
    4. Patient should be at least 12 hours from last short-acting or 24 hours from last long-acting Opioid
    5. Clinical Opiate Withdrawal Scale (or other withdrawal scale)
      1. Avoid starting Buprenorphine in patients without active withdrawal symptoms
  2. Induction Phase (3-7 days)
    1. Started >12 hours after last short acting Narcotic
    2. Started >24 hours after last long acting Narcotic
    3. Monitor at 60 min interval after first dose, titrating to dose that reduces withdrawal symptoms
      1. Re-evaluation in 24 hours (no more than 7 days)
    4. Adjusted based on physician evaluation, withdrawal
      1. Day 1: 2 mg every 1-2 hours to max 8-12 mg/day
      2. By day 7: Maximum of 32 mg/day (no benefit above 24-32 mg daily)
  3. Stabilization Phase (1-2 months)
    1. Identify minimum effective dose
    2. Typical: Buprenorphine 12-24 mg/day divided
  4. Maintenance Phase (indefinite)
    1. Dosing based on stabilization phase
    2. Evaluate compliance
      1. Review State prescription monitoring programs
      2. Random urine drug tests
      3. Pill counts
  5. Discontinuation
    1. Slowly taper (unless discontinued for diversion)

XIV. Management: Acute Pain Control for patients on Buprenorphine

  1. Non-Opioids
    1. Acetaminophen
    2. NSAIDs
    3. Topical agents (e.g. Lidocare or Lidocaine Patch)
  2. Opioids
    1. Divide Buprenorphine dosing every 6-8 hours (maximum daily dosing up to 32 mg)
    2. May add short acting Opioids (e.g. Morphine), but risk of relpase
    3. (2017) Presc Lett 24(1): 2-3

XV. Resources

  1. SAMHSA Buprenorphine information
    1. http://buprenorphine.samhsa.gov/

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Cost: Medications

buprenorphine (on 5/17/2017 at Medicaid.Gov Survey of pharmacy drug pricing)
suboxone (on 1/2/2017 at Medicaid.Gov Survey of pharmacy drug pricing)
SUBOXONE 12 MG-3 MG SL FILM $14.98 each
SUBOXONE 2 MG-0.5 MG SL FILM $4.18 each
SUBOXONE 4 MG-1 MG SL FILM $7.52 each
SUBOXONE 8 MG-2 MG SL FILM $7.46 each
zubsolv (on 2/22/2017 at Medicaid.Gov Survey of pharmacy drug pricing)
ZUBSOLV 1.4-0.36 MG TABLET SL $3.76 each
ZUBSOLV 2.9-0.71 MG TABLET SL $7.56 each
ZUBSOLV 5.7-1.4 MG TABLET SL $7.53 each
ZUBSOLV 8.6-2.1 MG TABLET SL $11.28 each
butrans (on 2/22/2017 at Medicaid.Gov Survey of pharmacy drug pricing)
BUTRANS 10 MCG/HR PATCH $88.38 each
BUTRANS 15 MCG/HR PATCH $127.63 each
BUTRANS 20 MCG/HR PATCH $156.14 each
BUTRANS 5 MCG/HR PATCH $58.83 each
BUTRANS 7.5 MCG/HR PATCH $82.64 each
belbuca (on 3/1/2017 at Medicaid.Gov Survey of pharmacy drug pricing)
BELBUCA 150 MCG FILM $4.52 each
BELBUCA 300 MCG FILM $6.99 each
BELBUCA 450 MCG FILM $9.53 each
BELBUCA 75 MCG FILM $4.44 each

Ontology: Subutex (C0006404)

Concepts Pharmacologic Substance (T121) , Organic Chemical (T109)
MSH D002047
English Temgesic, subutex, temgesic, Essex Brand of Buprenorphine Hydrochloride, Reckitt Benckiser Brand of Buprenorphine Hydrochloride, Reckitt Brand of Buprenorphine Hydrochloride, Schering Plough Brand of Buprenorphine Hydrochloride, Schering-Plough Brand of Buprenorphine Hydrochloride, Subutex, Buprenorphine Grünenthal Brand, Grünenthal Brand of Buprenorphine Hydrochloride, Grünenthal Brand of Buprenorphine, Temgésic, Buprex, Reckitt & Colman Brand 2 of Buprenorphine Hydrochloride
Czech suboxon, subutex

Ontology: Buprenorphine (C0006405)

Definition (MSH) A derivative of the opioid alkaloid THEBAINE that is a more potent and longer lasting analgesic than MORPHINE. It appears to act as a partial agonist at mu and kappa opioid receptors and as an antagonist at delta receptors. The lack of delta-agonist activity has been suggested to account for the observation that buprenorphine tolerance may not develop with chronic use.
Definition (CSP) 21-cyclopropyl-7-alpha-(2-hydroxy-3, 3-dimethyl-2-butyl)-6,14-endo-ethano -6,7,8,14-tetrahydro oripavine, a narcotic analgesic with mixed agonist-antagonist opiate properties; potential efficacy in heroin withdrawal.
Concepts Pharmacologic Substance (T121) , Organic Chemical (T109)
MSH D002047
SnomedCT 370250006, 31684002, 387173000
LNC LP16054-6, MTHU006723
English Buprenorphine, 6,14-Ethenomorphinan-7-methanol, 17-(cyclopropylmethyl)-alpha-(1,1-dimethylethyl)-4,5-epoxy-18,19-dihydro-3-hydroxy-6-methoxy-alpha-methyl-, (5alpha,7alpha(S))-, Buprenorphine [Chemical/Ingredient], BUPRENORPHINE, buprenorphine, Buprenorphine product, Buprenorphine product (product), Buprenorphine (product), Buprenorphine (substance)
Swedish Buprenorfin
Czech buprenorfin
Finnish Buprenorfiini
Japanese ザルバン, レペタン, 塩酸ブプレノルフィン, ブプレノルフィン
Polish Buprenorfina
Spanish producto con buprenorfina, producto con buprenorfina (producto), buprenorfina (producto), buprenorfina (sustancia), buprenorfina, Buprenorfina
French Buprénorphine
German Buprenorphin
Italian Buprenorfina
Portuguese Buprenorfina

Ontology: Suboxone (C1170625)

Concepts Pharmacologic Substance (T121) , Organic Chemical (T109)
MSH C510748
English suboxone, Suboxone